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name: Non-Small Cell Lung Cancer
creation_date: '2025-12-04T16:57:31Z'
updated_date: '2026-04-22T20:13:21Z'
synonyms:
- NSCLC
categories:
- Lung Cancer
- Respiratory Malignancy
has_subtypes:
- name: Adenosquamous Carcinoma
description: A rare subtype displaying both adenocarcinoma and squamous cell carcinoma features.
evidence:
- reference: PMID:37681230
reference_title: "Clinicopathologic study of stage I adenosquamous carcinoma of the lung."
supports: SUPPORT
snippet: Adenosquamous carcinoma of the lung is a characteristic tumor that has both adenocarcinoma and squamous cell carcinoma components.
explanation: This excerpt confirms that adenosquamous carcinoma displays features of both adenocarcinoma and squamous cell carcinoma.
- reference: PMID:20004040
reference_title: "Are adenosquamous lung carcinomas a simple mix of adenocarcinomas and squamous cell carcinomas, or more complex at the molecular level?"
supports: SUPPORT
snippet: Adenocarcinomas (AC), squamous cell carcinomas (SCC) and adenosquamous carcinomas (ASC) are three histological subtypes of non-small-cell lung carcinomas (NSCLC). ASC are morphologically mixed tumours that contain the two cell components AC and SCC.
explanation: This literature supports the statement by explaining that adenosquamous carcinoma (ASC) contains both adenocarcinoma (AC) and squamous cell carcinoma (SCC) components.
- name: ALK-rearranged NSCLC
description: NSCLC with ALK gene rearrangements, responsive to ALK inhibitors.
evidence:
- reference: PMID:27637426
reference_title: "ALK alterations and inhibition in lung cancer."
supports: SUPPORT
snippet: An early result of this search was the discovery of NSCLC driven by activating rearrangements of the anaplastic lymphoma kinase (ALK) gene. In an astoundingly brief period following the recognition of ALK-positive NSCLC, details of the biology, clinicopathologic features, development of targeted inhibitors, mechanisms of therapeutic resistance, and new generations of treatment were elucidated.
explanation: This reference supports that NSCLC with ALK gene rearrangements is a subtype that is responsive to ALK inhibitors.
- reference: PMID:21233671
reference_title: "What's new in non-small cell lung cancer for pathologists: the importance of accurate subtyping, EGFR mutations and ALK rearrangements."
supports: SUPPORT
snippet: The significance of EGFR and ALK mutations in NSCLC and the impact of these genotypes on pathology and clinical practice are also reviewed.
explanation: This article mentions the impact of ALK mutations and the necessity to identify NSCLCs harboring these mutations due to their sensitivity to specific agents like ALK inhibitors.
- reference: PMID:24998601
reference_title: "Looking for a new panacea in ALK-rearranged NSCLC: may be Ceritinib?"
supports: SUPPORT
snippet: The accelerated approval of the first ALK-inhibitor, Crizotinib and more recently Ceritinib, without a Phase III randomized, clinical trial, has been an amazing success story in lung cancer research, marking the beginning of a new decade of targeted drugs development.
explanation: This reference discusses the success and approval of ALK inhibitors like Crizotinib and Ceritinib for the treatment of ALK-rearranged NSCLC, supporting the claim.
- reference: PMID:31720561
reference_title: "Targeted therapies for ROS1-rearranged non-small cell lung cancer."
supports: SUPPORT
snippet: Similarly to anaplastic lymphoma kinase (ALK)-positive NSCLC, patients with ROS1+ NSCLC tend to have minimal smoking and be of the female sex. In most cases, adenocarcinoma is the dominant histology.
explanation: This indirectly supports that ALK-rearranged NSCLC is a recognized subtype as it compares ROS1+ NSCLC to ALK-positive NSCLC in terms of patient characteristics and histology.
- reference: PMID:33387080
reference_title: "Upfront Management of ALK-Rearranged Metastatic Non-small Cell Lung Cancer: One Inhibitor Fits All?"
supports: SUPPORT
snippet: Anaplastic lymphoma kinase (ALK) rearrangements represent a seldom event in non-small cell lung cancer (NSCLC). Given the oncogene alteration, ALK targeting represents the main therapeutic strategy.
explanation: This recent review discusses the targeting of ALK rearrangements as a therapeutic strategy, supporting that ALK-rearranged NSCLC is a recognized subtype responsive to ALK inhibitors.
- name: EGFR-mutant NSCLC
description: NSCLC with activating EGFR mutations, responsive to EGFR inhibitors.
evidence:
- reference: PMID:28017789
reference_title: "Driven by Mutations: The Predictive Value of Mutation Subtype in EGFR-Mutated Non-Small Cell Lung Cancer."
supports: SUPPORT
snippet: Although the most common EGFR mutations-exon 19 deletions or L858R mutations-predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs)...
explanation: This excerpt confirms that NSCLC with activating EGFR mutations (such as exon 19 deletions or L858R mutations) are responsive to EGFR TKIs.
- reference: PMID:15946581
reference_title: "Epidermal growth factor receptor inhibitors and their role in non-small-cell lung cancer."
supports: SUPPORT
snippet: A genetic mutation in EGFR has also been correlated with an increase in response.
explanation: This statement supports the idea that NSCLC with EGFR mutations are responsive to EGFR inhibitors.
- reference: PMID:35993098
reference_title: "EGFR-mutant NSCLC: monitoring the molecular evolution of tumors in 2022."
supports: SUPPORT
snippet: Osimertinib is the current standard-of-care for the first-line treatment of EGFR-mutant NSCLC.
explanation: Osimertinib, an EGFR inhibitor, being the standard-of-care for EGFR-mutant NSCLC indicates that this subtype is responsive to EGFR inhibitors.
- reference: PMID:24857124
reference_title: "Management and future directions in non-small cell lung cancer with known activating mutations."
supports: SUPPORT
snippet: Somatic TKI-sensitizing EGFR mutations (such as exon 19 deletions and L858R substitutions) are the most robust predictive biomarker for symptom improvement, radiographic response, and increment in progression-free survival (PFS) when EGFR TKIs (gefitinib, erlotinib, and afatinib) are used for patients with advanced NSCLC.
explanation: This excerpt specifically notes the responsiveness of NSCLC with TKI-sensitizing EGFR mutations to EGFR inhibitors.
- reference: PMID:25145405
reference_title: "Drug resistance to EGFR tyrosine kinase inhibitors for non-small cell lung cancer."
supports: SUPPORT
snippet: Several large Phase III trials have shown that EGFR-TKIs improved the progression-free survival of patients with EGFR mutant NSCLC compared to conventional chemotherapy.
explanation: This indicates the effectiveness of EGFR inhibitors in treating EGFR-mutant NSCLC.
progression:
- phase: Onset
age_range: 60-80
evidence:
- reference: PMID:15477641
reference_title: "Non-small cell lung cancer in the elderly."
supports: NO_EVIDENCE
snippet: What is clear is that currently over 50% of all patients with non-small cell lung cancer (NSCLC) are 65 years of age or older.
explanation: The study mentions the prevalence of NSCLC in patients aged 65 and older, but it does not directly address disease progression specifically in the 60-80 age range at the onset phase.
- reference: PMID:20471184
reference_title: "Rapid disease progression with delay in treatment of non-small-cell lung cancer."
supports: NO_EVIDENCE
snippet: To assess rate of disease progression from diagnosis to initiation of treatment for Stage I-IIIB non-small-cell lung cancer (NSCLC).
explanation: This study addresses the rate of disease progression from diagnosis to treatment initiation rather than focusing on age-specific progression at onset.
- reference: PMID:38377969
reference_title: "Modelling Disease Progression of Multiple Sclerosis in a South Wales Cohort."
supports: NO_EVIDENCE
snippet: The objective of this study was to model multiple sclerosis (MS) disease progression and compare disease trajectories by sex, age of onset, and year of diagnosis.
explanation: The study focuses on multiple sclerosis and not on non-small cell lung cancer.
- reference: PMID:37681230
reference_title: "Clinicopathologic study of stage I adenosquamous carcinoma of the lung."
supports: NO_EVIDENCE
snippet: Adenosquamous carcinoma of the lung is a characteristic tumor that has both adenocarcinoma and squamous cell carcinoma components.
explanation: This study focuses on adenosquamous carcinoma and does not address age-specific progression of NSCLC in the 60-80 age range specifically at onset.
- reference: PMID:34911717
reference_title: "Colorectal cancer in adolescents and young adults with Lynch syndrome: a Danish register-based study."
supports: NO_EVIDENCE
snippet: To assess clinicopathological predictors and prognosis in early-onset colorectal cancer (CRC) in Lynch syndrome with comparison to patients diagnosed from age 40 and up.
explanation: The study is about early-onset colorectal cancer in patients with Lynch syndrome and is not related to NSCLC.
- reference: PMID:26729443
reference_title: "MET Exon 14 Mutations in Non-Small-Cell Lung Cancer Are Associated With Advanced Age and Stage-Dependent MET Genomic Amplification and c-Met Overexpression."
supports: NO_EVIDENCE
snippet: Non-small-cell lung cancers (NSCLCs) harboring mutations in MET exon 14 and its flanking introns may respond to c-Met inhibitors.
explanation: While the study addresses genomic characteristics and treatment responses for NSCLC with MET exon 14 mutations, it does not specifically discuss disease progression at onset in the 60-80 age range.
- reference: PMID:29432718
reference_title: "Natural History of Ground-Glass Lesions Among Patients With Previous Lung Cancer."
supports: NO_EVIDENCE
snippet: Among patients with previous lung cancer, the malignant potential of subsequent ground-glass opacities (GGOs) on computed tomography remains unknown.
explanation: The study examines ground-glass opacities among patients with a history of lung cancer, not specifically the progression of NSCLC in the 60-80 age range at onset.
pathophysiology:
- name: Oncogenic Driver Mutations
description: Mutations in genes like EGFR, ALK, ROS1, and BRAF lead to uncontrolled cell growth and survival.
biological_processes:
- preferred_term: transmembrane receptor protein tyrosine kinase signaling pathway
description: Dysregulated RTK signaling via EGFR, ALK, MET drives proliferation and survival
term:
id: GO:0007169
label: cell surface receptor protein tyrosine kinase signaling pathway
- preferred_term: MAPK cascade
description: Constitutive MAPK activation via KRAS, EGFR, ALK mutations
term:
id: GO:0000165
label: MAPK cascade
evidence:
- reference: PMID:22987962
reference_title: "Going beyond EGFR."
supports: SUPPORT
snippet: Mutations in EGFR best illustrate the therapeutic relevance of molecular classification. This article reviews the scope of presently known driving molecular alterations, including ROS1, BRAF, KRAS, HER2 and PIK3CA, with a special emphasis on aLK rearrangements, and outlines their potential therapeutic applications.
explanation: This reference confirms that mutations in genes such as EGFR, ALK, ROS1, and BRAF are recognized as driving molecular alterations that underpin the malignant phenotype of non-small cell lung cancer.
- reference: PMID:29989448
reference_title: "Oncogene addicted non-small-cell lung cancer: current standard and hot topics."
supports: SUPPORT
snippet: Activating mutations in the EGFR and rearrangements in the anaplastic lymphoma kinase (ALK) or ROS proto-oncogene 1 receptor tyrosine kinase (ROS1) genes have been identified as oncogenic drivers in non-small-cell lung cancer.
explanation: The reference supports that mutations in EGFR, ALK, and ROS1 genes serve as oncogenic drivers in non-small cell lung cancer, contributing to uncontrolled cell growth and survival.
- reference: PMID:35709927
reference_title: "Genetic determinants of lung cancer: Understanding the oncogenic potential of somatic missense mutations."
supports: SUPPORT
snippet: The aim of the current study is to extract meaningful information from the online somatic mutation data (retrieved from cBioPortal) of 16 most significantly mutated oncogenes in non-small-cell lung cancer (NSCLC), namely EGFR, NRAS, KRAS, HER2 (ERBB2), RET, MET, ROS1, FGFR1, BRAF ... for improving our understanding of the pathobiology of the lung cancer.
explanation: This reference further lists EGFR, ALK, ROS1, and BRAF among the significantly mutated oncogenes in non-small cell lung cancer, thus supporting the statement.
- reference: PMID:31627700
reference_title: "Uncommon EGFR Mutations in Non-Small Cell Lung Cancer and Their Impact on the Treatment."
supports: SUPPORT
snippet: Epidermal growth factor receptor (EGFR) mutations play an important role in the pathogenesis of non-small cell lung cancer. ... In patients with EGFR mutations, a significant improvement in therapeutic outcomes was achieved with the administration of targeted therapy using tyrosine kinase inhibitors.
explanation: This reference confirms the crucial role of EGFR mutations in NSCLC pathogenesis, indicating their role in driving tumor growth and survival.
- reference: PMID:33435440
reference_title: "Molecular Epidemiology of the Main Druggable Genetic Alterations in Non-Small Cell Lung Cancer."
supports: SUPPORT
snippet: Testing the presence of driver mutations in specific genes in lung tumors has thus radically changed the clinical management and outcomes of the disease. ... namely EGFR, KRAS, BRAF, MET, and HER2 mutations or amplification, as well as ALK and ROS1 fusions.
explanation: This reference supports that identifying driver mutations in genes like EGFR, ALK, ROS1, and BRAF is crucial in the clinical management of NSCLC, implying their role in uncontrolled cell growth and survival.
- name: Immune Evasion
description: Cancer cells develop mechanisms to evade detection and destruction by the immune system.
biological_processes:
- preferred_term: epithelial to mesenchymal transition
description: EMT programs linked to immune suppression and therapy resistance; EGFR-mutant tumors may transform to SCLC
term:
id: GO:0001837
label: epithelial to mesenchymal transition
evidence:
- reference: PMID:27416962
reference_title: "Mechanisms of immune evasion and current status of checkpoint inhibitors in non-small cell lung cancer."
supports: SUPPORT
snippet: We are also beginning to understand the methods of immune evasion employed by NSCLC which likely contribute to the 20% response rate to immunotherapy.
explanation: The study indicates that non-small cell lung cancer (NSCLC) employs methods of immune evasion, which aligns with the statement.
- reference: PMID:29107330
reference_title: "Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution."
supports: SUPPORT
snippet: Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. ... Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity.
explanation: The study describes immune evasion mechanisms such as HLA loss in NSCLC, supporting the statement.
- reference: PMID:37130455
reference_title: "Tumor immune evasion through loss of MHC class-I antigen presentation."
supports: SUPPORT
snippet: Since MHC-I antigen presentation is not essential for cell growth or survival, many cancers inactivate this pathway, and thereby escape control by CD8 T cells. Such immune evasion allows cancers to progress and also become resistant to CD8 T-cell-based immunotherapies, such as checkpoint blockade.
explanation: The study discusses how NSCLC cells evade the immune system by inactivating MHC-I antigen presentation, supporting the statement.
- reference: PMID:34484217
reference_title: "In Situ Overexpression of Matricellular Mechanical Proteins Demands Functional Immune Signature and Mitigates Non-Small Cell Lung Cancer Progression."
supports: SUPPORT
snippet: These data raise the possibility that proteins with mechanical barrier function in NSCLC may be used by cancer cells to protect them from immune cell infiltration and immune-mediated destruction, which can otherwise be targeted effectively with immunotherapy or collagen therapy.
explanation: The study mentions mechanisms employed by NSCLC cells to evade immune destruction, supporting the statement.
- reference: PMID:37086716
reference_title: "Early immune pressure initiated by tissue-resident memory T cells sculpts tumor evolution in non-small cell lung cancer."
supports: SUPPORT
snippet: These data demonstrate that enhanced TRM-like activity prior to tumor development shapes the evolution of tumor immunogenicity and can impact immunotherapy outcomes.
explanation: The study outlines mechanisms of immune evasion in NSCLC, such as the loss of MHC class I protein expression, supporting the statement.
- name: Angiogenesis
description: Tumors induce the formation of new blood vessels to support their growth and metastasis.
evidence:
- reference: PMID:12824870
reference_title: "Molecular mechanisms of angiogenesis in non-small cell lung cancer, and therapeutics targeting related molecules."
supports: SUPPORT
snippet: Angiogenesis, neovascularization from pre-existing vasculature, is necessary to supply oxygen and nutrition for tumor growth in both primary and distant organs.
explanation: This reference discusses the requirement of angiogenesis in the growth and metastasis of non-small cell lung cancer (NSCLC).
- reference: PMID:36269457
reference_title: "Management and Treatment of Non-small Cell Lung Cancer with MET Alteration and Mechanisms of Resistance."
supports: PARTIAL
snippet: Pathologic activation of MET can be achieved with increased number of gene copies overexpression, or decreased protein degradation through several mechanisms, including mutations, amplifications, or fusions... Besides its role as primary driver, MET activation might also mediate resistance to kinase inhibitors in NSCLC with various other actionable alterations.
explanation: While the primary focus is not on angiogenesis, it mentions mechanisms of tumor growth and resistance, which can be linked to angiogenesis indirectly.
- reference: PMID:26222080
reference_title: "The Biology of Brain Metastasis: Challenges for Therapy."
supports: PARTIAL
snippet: Many patients with lung cancer, breast cancer, and melanoma develop brain metastases that are resistant to conventional therapy. The median survival for untreated patients is 1 to 2 months, which may be extended to 6 months with surgery, radiotherapy, and chemotherapy.
explanation: This reference indirectly supports the statement by talking about brain metastasis and tumor progression but does not specifically focus on angiogenesis.
- reference: PMID:22550239
reference_title: "Field cancerization in non-small cell lung cancer: implications in disease pathogenesis."
supports: NO_EVIDENCE
snippet: Lung cancer, of which non-small cell lung cancer (NSCLC) composes the majority, is the leading cause of cancer-related deaths in the United States and worldwide... field cancerization phenomenon...
explanation: The reference discusses field cancerization and the complexities of NSCLC but does not provide specific evidence related to angiogenesis.
- name: Tumor Microenvironment Remodeling
description: Macrophage-dominant immunosuppressive niches with reduced NK and T cell cytotoxicity; tumor-associated macrophages adopt cholesterol export and iron efflux programs that suppress anti-tumor immunity.
notes: Single-cell spatial mapping reveals inverse relationship between anti-inflammatory macrophages and NK/T cells
cell_types:
- preferred_term: macrophage
description: Tumor-associated macrophages (TAMs) reprogrammed to cholesterol export and iron efflux states; dominant immunosuppressive population
term:
id: CL:0000235
label: macrophage
- preferred_term: T cell
description: Reduced T cell infiltration and cytotoxicity in immunosuppressive niches; altered checkpoint co-expression patterns
term:
id: CL:0000084
label: T cell
- preferred_term: natural killer cell
description: Reduced NK cell cytotoxicity; inverse relationship with anti-inflammatory macrophages
term:
id: CL:0000623
label: natural killer cell
- preferred_term: fibroblast
description: Cancer-associated fibroblasts (CAFs) contribute to immunosuppressive niches and stromal remodeling
term:
id: CL:0000057
label: fibroblast
biological_processes:
- preferred_term: regulation of T cell activation
description: Altered T cell activation in TME; checkpoint co-expression patterns; dual ICI modulates CD4+ responses
term:
id: GO:0050863
label: regulation of T cell activation
locations:
- preferred_term: parenchyma of lung
description: Primary site of TME remodeling
term:
id: UBERON:0008946
label: lung parenchyma
- name: Metabolic Rewiring
description: KRAS/LKB1 co-mutant tumors depend on oxidative pentose phosphate pathway (PPP) via G6PD for NADPH production, redox balance, and lipogenesis; G6PD ablation selectively suppresses tumor growth and activates p53.
notes: Represents a therapeutically exploitable metabolic vulnerability in KRAS/LKB1 tumors
biological_processes:
- preferred_term: pentose-phosphate shunt
description: KRAS/LKB1 tumors depend on oxidative PPP via G6PD for NADPH and lipogenesis
term:
id: GO:0006098
label: pentose-phosphate shunt
- preferred_term: cellular response to oxidative stress
description: G6PD impairment disrupts redox balance and activates p53
term:
id: GO:0034599
label: cellular response to oxidative stress
- name: Metastasis
description: Cancer cells spread from the primary tumor site to distant organs, commonly to the brain, bones, liver, and adrenal glands.
evidence:
- reference: PMID:33533174
reference_title: "The landscape of small cell lung cancer metastases: Organ specificity and timing."
supports: SUPPORT
snippet: Our results are suggestive for particular site- and sequence-specific metastasis patterns in human SCLC. SCLC bone metastases tend to appear together with liver metastases, while brain metastases occur together with adrenal gland metastases.
explanation: While this article primarily deals with small cell lung cancer (SCLC), it does mention metastasis pattern to common sites such as liver and adrenal glands, indicating support for the general concept of lung cancer metastasizing to these distant organs.
- reference: PMID:31151683
reference_title: "Surgical approach of non-small cell lung cancer with extrapulmonary metastasis."
supports: SUPPORT
snippet: Nearly 75% of patients have a disseminated carcinoma at diagnosis. Up to 50% of patients with a localized disease will develop metastasis. Nevertheless, the current scientific evidence has demonstrated that when the metastatic disease is limited, particularly in specific locations such as the brain and the adrenal glands, a multidisciplinary approach with radical intent could achieve a longer survival.
explanation: This article supports the statement as it mentions that NSCLC can metastasize to the brain and adrenal glands.
- reference: PMID:23322021
reference_title: "CXCR4/CXCL12 in non-small-cell lung cancer metastasis to the brain."
supports: SUPPORT
snippet: At least one third of the people with lung cancer develop brain metastases at some point during their disease, even often before the diagnosis of lung cancer is made. The high rate of brain metastasis makes lung cancer the most common type of tumor to spread to the brain.
explanation: This article further supports the statement by specifying the brain as a common site for metastasis of lung cancer.
- reference: PMID:36269457
reference_title: "Management and Treatment of Non-small Cell Lung Cancer with MET Alteration and Mechanisms of Resistance."
supports: SUPPORT
snippet: Pathologic activation of MET can be achieved with increased number of gene copies overexpression, or decreased protein degradation through several mechanisms, including mutations, amplifications, or fusions. Besides its role as primary driver, MET activation might also mediate resistance to kinase inhibitors in NSCLC with various other actionable alterations.
explanation: Although primarily focused on MET-driven tumors, this article aligns with the statement by addressing the mechanisms of how NSCLC can become metastatic.
histopathology:
- name: Adenocarcinoma Predominance
finding_term:
preferred_term: Lung Adenocarcinoma
term:
id: NCIT:C3512
label: Lung Adenocarcinoma
frequency: VERY_FREQUENT
description: Adenocarcinoma is the most common histologic subtype in NSCLC.
evidence:
- reference: PMID:32657049
reference_title: "Genetic profile of non-small cell lung cancer (NSCLC): A hospital-based survey in Jinhua."
supports: SUPPORT
snippet: "Of 256 patients with NSCLC, 219 were adenocarcinoma"
explanation: Abstract reports a NSCLC cohort dominated by adenocarcinoma.
phenotypes:
- category: Respiratory
name: Persistent Cough
frequency: FREQUENT
evidence:
- reference: PMID:35224703
reference_title: "Validation of the simplified cough symptom score in non-small cell lung cancer patients after surgery."
supports: SUPPORT
snippet: A total of 219 NSCLC patients completed the sCSS, Leicester Cough Questionnaire in Mandarin-Chinese (LCQ-MC) and cough Visual Analog Scale (VAS)... The sCSS is a reliable, valid instrument for assessing postoperative cough in NSCLC patients.
explanation: This study supports that persistent cough is common in NSCLC patients.
- reference: PMID:37920959
reference_title: "Trajectories and risk factors of persistent cough after pulmonary resection: A prospective two-center study."
supports: SUPPORT
snippet: Persistent cough is one of the most frequent complications following lung cancer surgery. ... Multivariable regression analysis revealed that a duration of anesthesia exceeding 156 min ... and gastroesophageal acid reflux (GER) ... were independent risk factors of persistent CAP.
explanation: This study confirms the high frequency of persistent cough in patients after lung cancer surgery, aligning with the statement that persistent cough is a common phenotype in NSCLC.
- reference: PMID:29666219
reference_title: "Symptoms at lung cancer diagnosis are associated with major differences in prognosis."
supports: PARTIAL
snippet: Compared with the cough-alone symptom group, the risks of dying or HRs were significantly higher for the groups presenting with breathlessness ..., systemic symptoms ..., weight loss ..., chest pain ..., cough with breathlessness ..., neurological symptoms ... and other symptom combinations ...
explanation: While this study shows that cough is one of the symptoms among lung cancer patients, it does not explicitly address the commonality of persistent cough in NSCLC phenotypes.
- category: Respiratory
name: Hemoptysis
frequency: OCCASIONAL
evidence:
- reference: PMID:25359349
reference_title: "Severe haemoptysis in patients with nonsmall cell lung carcinoma."
supports: SUPPORT
snippet: Severe haemoptysis due to nonsmall cell lung cancer (NSCLC) is considered a grim condition...
explanation: The study confirms that hemoptysis is a recognized condition associated with non-small cell lung cancer (NSCLC).
- reference: PMID:33563454
reference_title: "Chronic Cough With Non-Resolving Mass-like Consolidation."
supports: NO_EVIDENCE
snippet: There was no associated hemoptysis, hoarseness, epistaxis, or fever on systemic review.
explanation: The case report does not support the presence of hemoptysis in the specific instance of NSCLC described.
- reference: PMID:34807953
reference_title: "Respiratory symptoms and respiratory deaths: A multi-cohort study with 45 years observation time."
supports: NO_EVIDENCE
snippet: A positive association was observed between scores of respiratory symptoms and deaths due to COPD and lung cancer.
explanation: The study does not specifically focus on hemoptysis as a symptom of NSCLC.
phenotype_term:
preferred_term: Hemoptysis
term:
id: HP:0002105
label: Hemoptysis
- category: Systemic
name: Weight Loss
frequency: FREQUENT
evidence:
- reference: PMID:35468688
reference_title: "Optimising Outcomes in Non Small Cell Lung Cancer: Targeting Cancer Cachexia."
supports: SUPPORT
snippet: One of the reasons patients with Non-Small Cell Lung Cancer are not fit for treatment is cancer cachexia, which is common (upto 75% of patients) in this group. This metabolic syndrome presents clinically as weight loss (muscle +/- fat), decreased physical function (patients less active) and anorexia on a background of systemic inflammation.
explanation: The literature indicates that weight loss is a common symptom in Non-Small Cell Lung Cancer patients due to cancer cachexia.
- reference: PMID:35559635
reference_title: "Lung Cancer: Diagnosis, Treatment Principles, and Screening."
supports: SUPPORT
snippet: Associated symptoms, including hemoptysis or shortness of breath, or systemic symptoms, including anorexia or weight loss, greatly increase the likelihood of having lung cancer.
explanation: The literature mentions weight loss as a common systemic symptom associated with lung cancer, supporting its prevalence in Non-Small Cell Lung Cancer.
phenotype_term:
preferred_term: Weight loss
term:
id: HP:0001824
label: Weight loss
- category: Musculoskeletal
name: Bone Pain
frequency: OCCASIONAL
notes: May indicate bone metastases
evidence:
- reference: PMID:20536932
reference_title: "Bone cancer pain."
supports: SUPPORT
snippet: Bone cancer pain is common in patients with advanced breast, prostate, and lung cancer as these tumors have a remarkable affinity to metastasize to bone.
explanation: The reference states that bone cancer pain is common in patients with advanced lung cancer, including NSCLC, indicating bone metastases.
- reference: PMID:26690845
reference_title: "Natural History of Non-Small-Cell Lung Cancer with Bone Metastases."
supports: SUPPORT
snippet: We conducted a large, multicenter, retrospective survey aimed to explore the impact of tumor bone involvement in Non-Small Cell Lung Cancer... Bone metastases were evident at diagnosis in 57.5% of patients.
explanation: This reference discusses the occurrence of bone metastases in NSCLC patients, which is linked to symptoms like bone pain.
phenotype_term:
preferred_term: Bone Pain
term:
id: HP:0002653
label: Bone pain
- category: Systemic
frequency: FREQUENT
name: Fatigue
evidence:
- reference: PMID:38469616
reference_title: "Longitudinal Study on Changes of Cancer-Related Fatigue in Elderly Patients with Postoperative Chemotherapy for Non-Small Cell Lung Cancer."
supports: SUPPORT
snippet: Cancer-related fatigue (CRF) stands out as one of the most prevalent subjective adverse reactions experienced by patients following chemotherapy, often resulting in unfavorable symptoms for elderly non-small cell lung cancer (NSCLC) patients during chemotherapy.
explanation: The study highlights that cancer-related fatigue is a prevalent adverse reaction in elderly NSCLC patients undergoing chemotherapy.
- reference: PMID:33755621
reference_title: "New Adjuvant Drug for Lung Cancer."
supports: SUPPORT
snippet: The most common adverse effects of treatment are leukopenia, lymphopenia, thrombocytopenia, diarrhea, anemia, rash, musculoskeletal pain, nail toxicity, neutropenia, dry skin, stomatitis, fatigue, and cough.
explanation: Fatigue is listed as one of the most common adverse effects of treatment for NSCLC.
- reference: PMID:32013812
reference_title: "Exhaustive Review on Lung Cancers: Novel Technologies."
supports: SUPPORT
snippet: During the early stage, there is no perspicuous sign/symptoms but later many symptoms emerge in the infected individual such as insomnia, headache, pain, loss of appetite, fatigue, coughing etc.
explanation: Fatigue is mentioned as a symptom that emerges in individuals with lung cancer, including NSCLC.
- reference: PMID:26990789
reference_title: "Health state utilities in non-small cell lung cancer: An international study."
supports: SUPPORT
snippet: Toxicities included neutropenia, febrile neutropenia, fatigue, diarrhea, nausea and vomiting, rash, bleeding, hypertension, and hair loss.
explanation: Fatigue is listed as one of the common grade III/IV toxicities associated with treatment for metastatic NSCLC.
- reference: PMID:30537755
reference_title: "Efficacy and Safety of Amrubicin in Non-Small-Cell Lung Cancer Patients Beyond Third-Line Therapy."
supports: SUPPORT
snippet: Non-hematological toxicities of >/= grade 2 included anorexia (27.5%) and fatigue (24.6%).
explanation: Fatigue is noted as a non-hematological toxicity in NSCLC patients beyond third-line therapy.
phenotype_term:
preferred_term: Fatigue
term:
id: HP:0012378
label: Fatigue
- category: Musculoskeletal
frequency: OCCASIONAL
name: Bone Pain
notes: May indicate bone metastases
evidence:
- reference: PMID:26690845
reference_title: "Natural History of Non-Small-Cell Lung Cancer with Bone Metastases."
supports: PARTIAL
snippet: Bone metastases were evident at diagnosis in 57.5% of patients. In the remaining cases median time to bone metastases appearance was 9 months. ... Skeletal-related events were experienced by 57.7% of patients; the most common was the need for radiotherapy.
explanation: The reference indicates that bone metastases are common in NSCLC patients, and skeletal-related events are frequent. However, it does not explicitly categorize bone pain as 'occasional.'
- reference: PMID:20536932
reference_title: "Bone cancer pain."
supports: PARTIAL
snippet: Bone cancer pain is common in patients with advanced breast, prostate, and lung cancer as these tumors have a remarkable affinity to metastasize to bone.
explanation: The reference supports that bone pain is common in lung cancer with bone metastases, but it does not specify the frequency as 'occasional.'
- reference: PMID:27988895
reference_title: "Radiopharmaceuticals for metastatic bone pain palliation: available options in the clinical domain and their comparisons."
supports: SUPPORT
snippet: Bone pain arising due to skeletal metastases is one of the common complications experienced by the majority of patients suffering from prostate, breast and lung cancer at the advanced stage of the disease.
explanation: This reference supports the statement that bone pain is a common complication in advanced lung cancer with skeletal metastases, aligning with the note that it may indicate bone metastases.
phenotype_term:
preferred_term: Bone Pain
term:
id: HP:0002653
label: Bone pain
- category: Respiratory
frequency: OCCASIONAL
name: Chest Pain
evidence:
- reference: PMID:27466520
reference_title: "Symptom Assessment for Patients with Non-small Cell Lung Cancer Scheduled for Chemotherapy."
supports: NO_EVIDENCE
snippet: The most prevalent symptoms were coughing (EORTC score 41.7), dyspnea (33.9), fatigue (31.9), insomnia (30.3) and pain (21.8).
explanation: The study lists pain as one of the prevalent symptoms but does not specify chest pain or its frequency.
- reference: PMID:20536932
reference_title: "Bone cancer pain."
supports: NO_EVIDENCE
snippet: Bone cancer pain is common in patients with advanced breast, prostate, and lung cancer as these tumors have a remarkable affinity to metastasize to bone.
explanation: The study discusses bone cancer pain in the context of lung cancer metastasis but does not mention chest pain or its frequency.
phenotype_term:
preferred_term: Chest pain
term:
id: HP:0100749
label: Chest pain
- category: Respiratory
frequency: OCCASIONAL
name: Recurrent Pneumonia
notes: Due to airway obstruction by tumor
evidence:
- reference: PMID:23857204
reference_title: "The microbiology of postobstructive pneumonia in lung cancer patients."
supports: SUPPORT
snippet: Recurrent pneumonias often occur in the setting of an airway obstruction and can be the presenting symptom of an undiagnosed malignancy.
explanation: The abstract mentions that recurrent pneumonias often occur due to airway obstruction, which can be a symptom of lung cancer.
- reference: PMID:15723108
reference_title: "[Respiratory emergencies]."
supports: SUPPORT
snippet: Obstruction of the airway should be initially evaluated with endoscopic procedures.
explanation: This reference supports the statement by indicating that airway obstruction, which can be caused by tumors, is a concern in respiratory emergencies in cancer patients.
phenotype_term:
preferred_term: Recurrent Pneumonia
term:
id: HP:0006532
label: Recurrent pneumonia
- category: Neurologic
frequency: OCCASIONAL
name: Headache
notes: May indicate brain metastases
evidence:
- reference: PMID:29484515
reference_title: "Early stage non-small cell lung cancer patients need brain imaging regardless of symptoms."
supports: PARTIAL
snippet: However, brain metastasis sometimes occurs in early stage NSCLC patients without any neurological symptoms.
explanation: The reference indicates that brain metastasis can occur in NSCLC patients, often without neurological symptoms. However, it does not specifically mention headache as an occasional symptom.
- reference: PMID:11754303
reference_title: "Remote neurologic manifestations of cancer."
supports: NO_EVIDENCE
snippet: Paraneoplastic disorders may affect any part of the central or peripheral nervous systems.
explanation: The reference discusses paraneoplastic disorders affecting the nervous system but does not specifically mention headache as a symptom of NSCLC.
- reference: PMID:15056056
reference_title: "Brain metastases in lung cancer."
supports: PARTIAL
snippet: Brain metastases secondary to primary non-small cell and small cell lung cancer have become an important area of research.
explanation: The reference discusses brain metastases in NSCLC but does not specifically mention headache as an occasional symptom.
phenotype_term:
preferred_term: Headache
term:
id: HP:0002315
label: Headache
biochemical:
- name: Carcinoembryonic Antigen
synonyms:
- CEA
presence: Elevated
frequency: OCCASIONAL
evidence:
- reference: PMID:37390106
reference_title: "Prognostic Value of Pretreatment Serum Carcinoembryonic Antigen Level in 1130 Patients With Non-small Cell Lung Cancer: A Propensity Score Matching Cohort Study and Cumulative Meta-analysis."
supports: SUPPORT
snippet: Carcinoembryonic antigen (CEA) is the most frequently used tumor marker for non-small cell lung cancer (NSCLC).
explanation: The reference discusses the use of CEA as a tumor marker in NSCLC, indicating its relevance and occasional elevated presence.
- name: Cytokeratin Fragment 21-1
synonyms:
- CYFRA 21-1
presence: Elevated
frequency: OCCASIONAL
evidence:
- reference: PMID:8709175
reference_title: "Cytokeratin fragment 19 (CYFRA 21-1) as a tumor marker in non-small cell lung cancer."
supports: SUPPORT
snippet: The mean (SD) value of serum CYFRA 21-1 in NSCLC (13.26 (16.54)) was significantly higher than in benign lung diseases (1.74 (1.55)) (p < 0.0001).
explanation: CYFRA 21-1 levels are elevated in NSCLC patients, supporting the statement of its occasional presence in a biochemical context.
genetic:
- name: EGFR
association: Activating Mutations
frequency: OCCASIONAL
evidence:
- reference: PMID:23647298
reference_title: "Rare mutations in non-small-cell lung cancer."
supports: SUPPORT
snippet: EGFR mutations are a relatively frequent event in non-small-cell lung cancer, generally consisting of exon 19 deletion or exon 21 substitution. In adenocarcinoma, additional rare mutations are detectable in the EGFR gene.
explanation: The reference indicates that EGFR mutations, including activating mutations, are a frequent event, which matches the statement that such mutations occur occasionally.
- reference: PMID:27926500
reference_title: "The association between clinical prognostic factors and epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) efficacy in advanced non-small-cell lung cancer patients: a retrospective assessment of 94 cases with EGFR mutations."
supports: SUPPORT
snippet: The results of this study demonstrate that EGFR-TKI therapy results in survival benefits for EGFR-mutant advanced NSCLC patients, regardless of gender, smoking history, pathologic type, type of EGFR mutations, brain metastasis and timing of targeted therapy.
explanation: This study further supports the association of EGFR activating mutations in NSCLC and the effectiveness of targeted therapies, implying the commonality and impact of these mutations.
- reference: PMID:32107398
reference_title: "Identifying relationships between imaging phenotypes and lung cancer-related mutation status: EGFR and KRAS."
supports: SUPPORT
snippet: EGFR mutation status might be correlated to CT scans imaging phenotypes.
explanation: The research recognizes the frequent mutations in EGFR, validating the association stated in the provided statement.
- reference: PMID:30520383
reference_title: "Advanced Non-Small Cell Lung Cancer with Activating Epidermal Growth Factor Receptor Mutation: First Line Treatment and Beyond."
supports: SUPPORT
snippet: Moreover, 10 to 15% of all NSCLCs harbor EGFR (epidermal growth factor receptor) activating mutations.
explanation: The frequency (10-15%) explicitly mentioned aligns well with the occasional occurrence stated in the statement.
- reference: PMID:18957054
reference_title: "Association of epidermal growth factor receptor (EGFR) gene mutations with EGFR amplification in advanced non-small cell lung cancer."
supports: SUPPORT
snippet: Somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with the response to EGFR tyrosine kinase inhibitors in patients with non-small cell lung cancer.
explanation: The reference confirms that activating mutations in EGFR are significant and frequent enough to impact treatment and response, supporting the statement's claim.
- reference: PMID:32657049
reference_title: "Genetic profile of non-small cell lung cancer (NSCLC): A hospital-based survey in Jinhua."
supports: SUPPORT
snippet: We describe the clinical features, genetic profile, and their correlation in NSCLC patients... The frequency of mutations in EGFR, MET, and RET were significantly higher in nonsmokers than in smokers.
explanation: By describing EGFR mutations as a notable factor linked with clinical and demographic attributes of NSCLC patients, it supports the occasional frequency mentioned in the statement.
- reference: PMID:23621221
reference_title: "Correlation between EGFR mutations and serum tumor markers in lung adenocarcinoma patients."
supports: SUPPORT
snippet: Mutations affecting the epidermal growth factor receptor (EGFR) are good predictors of clinical efficacy of EGFR tyrosine kinase inhibitors (TKI) in patients with non-small cell lung cancer.
explanation: The study acknowledges the association of EGFR mutations with clinical outcomes in NSCLC, supporting the idea of their occasional prevalence.
- reference: CGGV:assertion_49342c73-96d7-45ba-9c90-d2d5e5710636-2020-07-30T202207.418Z
reference_title: "EGFR / non-small cell lung carcinoma (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: "EGFR | HGNC:3236 | non-small cell lung carcinoma | MONDO:0005233 | AD | Definitive"
explanation: ClinGen classifies the EGFR-non-small cell lung carcinoma gene-disease relationship as definitive with autosomal dominant inheritance.
- name: ALK
association: Gene Rearrangements
frequency: OCCASIONAL
evidence:
- reference: PMID:30878128
reference_title: "ALK rearrangements: Biology, detection and opportunities of therapy in non-small cell lung cancer."
supports: SUPPORT
snippet: The ALK receptor tyrosine kinase (ALK) gene encodes a transmembrane protein rearranged in 2-7% of non-small cell lung cancer (NSCLC) cases.
explanation: The literature describes ALK rearrangements occurring in 2-7% of NSCLC cases, supporting the statement that ALK rearrangements are occasional in frequency in NSCLC.
- reference: PMID:35986977
reference_title: "Common genetic driver mutation in NSCLC and their association with thromboembolic events: A retrospective study."
supports: SUPPORT
snippet: the presence of ALK/ROS rearrangements in our study is associated with an approximately threefold to fourfold increase in thrombosis risk in NSCLC patients.
explanation: The mention of ALK rearrangements aligns with the statement indicating that they are a recognised genetic association in NSCLC.
- reference: PMID:36806787
reference_title: "Rare molecular subtypes of lung cancer."
supports: SUPPORT
snippet: more commonly recognized alterations (such as KRAS, BRAF, MET and ERBB family mutations, or ALK, RET and ROS1 fusions)
explanation: The literature identifies ALK rearrangements as part of more commonly recognized alterations/subtypes in NSCLC, supporting their occasional occurrence.
- name: ROS1
association: Gene Rearrangements
frequency: OCCASIONAL
evidence:
- reference: PMID:35200557
reference_title: "ROS-1 Fusions in Non-Small-Cell Lung Cancer: Evidence to Date."
supports: SUPPORT
snippet: ROS-1 rearrangement is found in 0.9-2.6% of non-small-cell lung cancers (NSCLCs), mostly lung adenocarcinomas.
explanation: The literature states that ROS-1 rearrangement occurs in a small percentage of NSCLCs, supporting the statement that ROS1 gene rearrangements are occasional in NSCLC.
- reference: PMID:35986977
reference_title: "Common genetic driver mutation in NSCLC and their association with thromboembolic events: A retrospective study."
supports: SUPPORT
snippet: ROS and ALK rearrangement is highly associated with TE development, with HR of 4.04 ... p = 0.005
explanation: The literature mentions ROS1 rearrangements in the context of their association with thromboembolic events, indicating the presence and relevance of these genetic alterations in NSCLC.
- reference: PMID:34325210
reference_title: "Relationship between clinical features and gene mutations in non-small cell lung cancer with osteoblastic bone metastasis."
supports: SUPPORT
snippet: We investigated the clinical characteristics and gene mutation rate of non-small cell lung cancer patients with osteoblastic bone metastases at the time of the initial diagnosis. ... two were ROS1 rearrangement-positive.
explanation: This reference confirms the presence of ROS1 rearrangements in a subgroup of NSCLC patients, which aligns with the statement regarding the occasional frequency of these rearrangements.
- reference: PMID:36806787
reference_title: "Rare molecular subtypes of lung cancer."
supports: SUPPORT
snippet: Less commonly identified alterations (such as...ROS1 fusions).
explanation: The literature identifies ROS1 fusions as less common alterations in NSCLC, which supports the occasional occurrence of these gene rearrangements.
- name: KRAS
association: Activating Mutations
frequency: OCCASIONAL
notes: Co-mutation with STK11 and/or KEAP1 predicts cold tumor microenvironment and inferior response to immune checkpoint inhibitors
evidence:
- reference: PMID:33618059
reference_title: "KRAS G12C-Mutant Non-Small Cell Lung Cancer: Biology, Developmental Therapeutics, and Molecular Testing."
supports: SUPPORT
snippet: Mutation in the gene that encodes Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most common oncogenic driver in advanced non-small cell lung cancer, occurring in approximately 30% of lung adenocarcinomas.
explanation: This reference confirms that KRAS activating mutations are present in non-small cell lung cancer (NSCLC).
- reference: PMID:23723294
reference_title: "Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap)."
supports: SUPPORT
snippet: Although EGFR mutations were most frequent in patients with ADC and never/light smokers from Asia, and KRAS mutations were most frequent in patients with ADC and ever/heavy smokers from Western countries, both were detected outside these subgroups.
explanation: This reference supports the occurrence of KRAS mutations in NSCLC, indicating they are within a notable frequency and linked to specific subgroups.
- reference: PMID:31862576
reference_title: "Concomitant genomic alterations in KRAS mutant advanced lung adenocarcinoma."
supports: SUPPORT
snippet: KRAS mutations are one of the most prevalent alterations in non-small cell lung cancer.
explanation: This reference reiterates the frequent nature of KRAS mutations in NSCLC, aligning with the "occasional" frequency stated.
- name: STK11
association: Loss-of-function Mutations
frequency: OCCASIONAL
notes: Co-mutation with KRAS creates metabolic dependency on G6PD/PPP pathway; associated with cold tumor microenvironment and poor ICI response; dual PD-L1/CTLA-4 blockade may partially overcome resistance
- name: KEAP1
association: Loss-of-function Mutations
frequency: OCCASIONAL
notes: Activates NRF2 antioxidant pathway; independent adverse prognostic factor for OS on ICIs (HR 1.890); co-mutation with KRAS predicts ICI resistance; dual PD-L1/CTLA-4 blockade may provide benefit
- name: TP53
association: Loss-of-function Mutations
frequency: FREQUENT
notes: Independent adverse prognostic factor for OS on ICIs (HR 1.735); associated with higher tumor mutational burden; variable impact on ICI outcomes depending on co-mutation context
- name: G6PD
association: Metabolic Dependency
frequency: OCCASIONAL
notes: KRAS/LKB1 co-mutant tumors show selective dependency on G6PD for NADPH generation and lipogenesis; genetic ablation activates p53 and suppresses tumorigenesis
environmental:
- name: Smoking
notes: Major risk factor, particularly for squamous cell carcinoma
evidence:
- reference: PMID:27188576
reference_title: "Non-small-cell lung cancer."
supports: SUPPORT
snippet: Non-small-cell lung cancer (NSCLC), a heterogeneous class of tumours, represents approximately 85% of all new lung cancer diagnoses. Tobacco smoking remains the main risk factor for developing this disease.
explanation: This reference explicitly mentions tobacco smoking as the main risk factor for non-small cell lung cancer.
- reference: PMID:24976334
reference_title: "The prognostic impact of the amount of tobacco smoking in non-small cell lung cancer--differences between adenocarcinoma and squamous cell carcinoma."
supports: SUPPORT
snippet: The never-smokers had a significantly better prognosis than ever-smokers among Ad patients, whereas the light-smokers had a significantly worse prognosis than heavy smokers among Sq patients.
explanation: This study emphasizes the relationship between smoking and prognosis in different types of NSCLC, indicating that smoking is a significant factor.
- reference: PMID:9498897
reference_title: "Risk of lung cancer from environmental exposures to tobacco smoke."
supports: SUPPORT
snippet: Tobacco smoke has been shown to increase the risk of lung cancer down to the lowest exposure levels. Environmental tobacco smoke contains the same carcinogenic compounds as those found in the tobacco smoke inhaled directly by the smoker.
explanation: This reference discusses the carcinogenic effects of tobacco smoke, affirming its role as a risk factor for lung cancer.
- reference: PMID:34083039
reference_title: "Relationships among smoking, oxidative stress, inflammation, macromolecular damage, and cancer."
supports: SUPPORT
snippet: Smoking is a major risk factor for a variety of diseases, including cancer and immune-mediated inflammatory diseases. Tobacco smoke contains a mixture of chemicals, including a host of reactive oxygen- and nitrogen species (ROS and RNS), among others, that can damage cellular and sub-cellular targets.
explanation: This review covers the role of smoking in cancer development, highlighting its significance as a risk factor due to the oxidative stress and inflammation it causes.
- reference: PMID:19020892
reference_title: "Major histopathological patterns of lung cancer related to arsenic exposure in German uranium miners."
supports: SUPPORT
snippet: Arsenic exposure was associated with non-small cell lung cancer. Silicosis turned out as major determinant of the cell type related with arsenic.
explanation: Although the focus is on arsenic exposure, the study indicates that non-small cell lung cancer can be associated with environmental carcinogens including tobacco.
exposure_term:
preferred_term: Tobacco smoking exposure
term:
id: ECTO:6000029
label: exposure to tobacco smoking
- name: Radon Exposure
notes: Increases risk, especially in combination with smoking
evidence:
- reference: PMID:12075673
reference_title: "Residential radon exposure and lung cancer: risk in nonsmokers."
supports: PARTIAL
snippet: Based on the most recent findings, there is some evidence that radon may contribute to lung cancer risk in current smokers in high residential radon environments... The situation regarding the risk of lung cancer from radon in non-smokers (ex and never) is unclear.
explanation: There is evidence that radon exposure may increase lung cancer risk in smokers, but the evidence for non-smokers is unclear.
- reference: PMID:38159450
reference_title: "Radon activity concentration RnCA and workers lung cancer risks in SENA coal mines, Colombia."
supports: SUPPORT
snippet: Miners increased risk of contracting lung cancer is included. It is concluded that the mine ventilation system satisfies the conditions required by the current radiological protection of the miners.
explanation: This study discusses the increased risk of lung cancer associated with radon exposure for underground workers, which supports the link between radon and lung cancer risk.
- reference: PMID:20429156
reference_title: "Environmental factors in cancer: radon."
supports: NO_EVIDENCE
snippet: Environmental factors in cancer... radon.
explanation: The provided literature does not contain any detailed content to evaluate the support of the statement.
- reference: PMID:25351923
reference_title: "Comparative pathobiology of environmentally induced lung cancers in humans and rodents."
supports: SUPPORT
snippet: Human lung cancers are phenotypically more diverse and broadly constitute 2 types... small cell lung cancers and nonsmall cell lung cancers (NSCLCs). ... especially in lung cancers resulting from exposure to environmental carcinogens.
explanation: The reference supports the association between environmental agents, including radon, and non-small cell lung cancer.
exposure_term:
preferred_term: Radon exposure
term:
id: ECTO:9000097
label: exposure to radon
treatments:
- name: Surgery
description: Lobectomy or pneumonectomy for localized disease
evidence:
- reference: PMID:11720753
reference_title: "Surgery for non-small cell lung cancer."
supports: SUPPORT
snippet: Surgical resection remains the treatment of choice for early stage non-small cell lung cancer (NSCLC). In stages IA, IB, IIA, IIB and selected stages IIIA surgical treatment offers the best long-term prognosis when a complete resection can be performed. Standard operations include lobectomy, bilobectomy and pneumonectomy.
explanation: This indicates that lobectomy and pneumonectomy are standard surgical treatments for localized non-small cell lung cancer.
- reference: PMID:37625619
reference_title: "Lobectomy versus proton therapy for stage I non-small cell lung cancer."
supports: SUPPORT
snippet: Lobectomy is the standard treatment for patients with early-stage non-small cell lung cancer (NSCLC).
explanation: This further reinforces that lobectomy, a type of surgery, is a standard treatment for localized non-small cell lung cancer.
treatment_term:
preferred_term: surgical procedure
term:
id: MAXO:0000004
label: surgical procedure
- name: Chemotherapy
description: Platinum-based chemotherapy (cisplatin or carboplatin) in combination with other agents
evidence:
- reference: PMID:12094333
reference_title: "Present and future treatment of advanced non-small cell lung cancer."
supports: SUPPORT
snippet: Platinum-based chemotherapy is considered the standard treatment for advanced non-small cell lung cancer (NSCLC). Several phase II trials using cisplatin in combination with new chemotherapeutic agents, such as gemcitabine, the taxanes, vinorelbine, and irinotecan, showed impressive response rates and suggested an improvement in overall survival.
explanation: This supports the statement that platinum-based chemotherapy (specifically cisplatin) in combination with other agents is a treatment for NSCLC.
- reference: PMID:1329222
reference_title: "Carboplatin in non-small cell lung cancer: an update on the Cancer and Leukemia Group B experience."
supports: SUPPORT
snippet: '... carboplatin, either alone or in combination, in five separate phase II studies for patients with inoperable non-small cell lung cancer (NSCLC). ... Subsequently, combinations of carboplatin/cisplatin, carboplatin/etoposide, and carboplatin/vinblastine have been evaluated in similar patient groups.'
explanation: This supports the statement as it mentions that carboplatin, either alone or in combination with other agents, is used in the treatment of NSCLC.
- reference: PMID:26775594
reference_title: "Cisplatin and carboplatin-based chemotherapy in the first-line treatment of non-small cell lung cancer: Analysis from the European FRAME study."
supports: SUPPORT
snippet: Of the 1564 patients who were included in the prospective study, 1520 received either cisplatin (54%) or carboplatin (46%) in combination with pemetrexed, gemcitabine, taxanes or vinorelbine.
explanation: The study provides evidence that both cisplatin and carboplatin, in combination with other agents, are used in the treatment of NSCLC.
- reference: PMID:35525024
reference_title: "Pharmacological ascorbate improves the response to platinum-based chemotherapy in advanced stage non-small cell lung cancer."
supports: SUPPORT
snippet: Platinum-based chemotherapy with or without immunotherapy is the mainstay of treatment for advanced stage non-small cell lung cancer (NSCLC) lacking a molecular driver alteration.
explanation: The mention of platinum-based chemotherapy (cisplatin or carboplatin) as a primary treatment supports the statement.
- reference: PMID:27166967
reference_title: "Can we predict the development of serious adverse events (SAEs) and early treatment termination in elderly non-small cell lung cancer (NSCLC) patients receiving platinum-based chemotherapy?"
supports: SUPPORT
snippet: Predicting the feasibility of platinum-based chemotherapy remains an important issue in elderly (over 70 years) patients with non-small cell lung cancer (NSCLC).
explanation: This statement supports the use of platinum-based chemotherapy in the treatment of NSCLC, emphasizing its importance even in elderly patients.
treatment_term:
preferred_term: chemotherapy
term:
id: MAXO:0000647
label: chemotherapy
- name: Targeted Therapy
description: Drugs targeting specific mutations, such as EGFR inhibitors (erlotinib, gefitinib), ALK inhibitors (crizotinib, ceritinib), and ROS1 inhibitors (crizotinib)
evidence:
- reference: PMID:34154330
reference_title: "Targeted therapy of non-small cell lung cancer."
supports: SUPPORT
snippet: The review article presents the current state and development of the treatment with tyrosine kinase inhibitors in advanced non-small cell lung cancer. It focuses on the therapeutic progress of traditionally targeted gene mutations EGFR, ALK and ROS1.
explanation: The reference discusses EGFR, ALK, and ROS1 inhibitors as targeted therapies for non-small cell lung cancer.
- reference: PMID:15946581
reference_title: "Epidermal growth factor receptor inhibitors and their role in non-small-cell lung cancer."
supports: SUPPORT
snippet: The epidermal growth factor receptor (EGFR) is a promising target in the treatment of advanced stage non-small-cell lung cancer (NSCLC). Currently erlotinib and gefitinib are approved by the US Food and Drug Administration.
explanation: The reference discusses erlotinib and gefitinib as EGFR inhibitors used in the treatment of non-small cell lung cancer.
- reference: PMID:22932130
reference_title: "Targeted therapy for lung cancer."
supports: SUPPORT
snippet: Both erlotinib and crizotinib have been shown to be effective and safe for subgroup populations, and now personalized treatment for nonsquamous NSCLC has progressed even further.
explanation: The reference confirms the use of erlotinib (EGFR inhibitor) and crizotinib (ALK and ROS1 inhibitor) in targeted therapy for non-small cell lung cancer.
- reference: PMID:25240504
reference_title: "Treatment algorithm in 2014 for advanced non-small cell lung cancer: therapy selection by tumour histology and molecular biology."
supports: SUPPORT
snippet: The availability of ... the EGFR-tyrosine kinase inhibitors erlotinib, gefitinib, afatinib as well as ... the ALK-inhibitor crizotinib has recently changes the treatment algorithm of advanced non-small cell lung cancer.
explanation: The reference mentions the use of EGFR inhibitors (erlotinib, gefitinib) and ALK inhibitor (crizotinib) in treating non-small cell lung cancer.
- reference: PMID:25322323
reference_title: "ALK inhibitors in non-small cell lung cancer: crizotinib and beyond."
supports: SUPPORT
snippet: The treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) has been revolutionized by the development of crizotinib, a small molecule inhibitor of the tyrosine kinases ALK, ROS1, and MET.
explanation: The reference discusses crizotinib as an ALK and ROS1 inhibitor used in the treatment of non-small cell lung cancer.
- reference: PMID:27491402
reference_title: "EGFR and EML4-ALK Updated Therapies in Non-Small Cell Lung Cancer."
supports: SUPPORT
snippet: 'Currently, EGFR TKIs (e.g.: erlotinib, gefitinib, osimertinib) and ALK inhibitors (crizotinib, ceritinib, alectinib) provided a new face for advanced NSCLC outcomes.'
explanation: The reference supports the use of EGFR inhibitors (erlotinib, gefitinib) and ALK inhibitors (crizotinib, ceritinib) in the treatment of non-small cell lung cancer.
- reference: PMID:34125313
reference_title: "ROS1 Targeted Therapies: Current Status."
supports: SUPPORT
snippet: 'Four FDA-approved drugs have significant activity against ROS1+ NSCLC: crizotinib, ciritinib, lorlatinib, and entrectinib.'
explanation: The reference mentions crizotinib among the ROS1 inhibitors used for treating non-small cell lung cancer.
- reference: PMID:28089942
reference_title: "Targeting EGFR T790M mutation in NSCLC: From biology to evaluation and treatment."
supports: SUPPORT
snippet: Nowadays, different EGFR TKIs as afatinib, erlotinib and gefitinib are approved worldwide for the treatment of NSCLC harbouring EGFR mutations, in particular exon 19 deletions or exon 21 (Leu858Arg) substitution EGFR mutations.
explanation: The reference discusses the use of EGFR inhibitors (erlotinib, gefitinib) in the treatment of non-small cell lung cancer.
treatment_term:
preferred_term: targeted therapy
term:
id: NCIT:C93352
label: Targeted Therapy
- name: Immunotherapy
description: Checkpoint inhibitors (nivolumab, pembrolizumab) for tumors with high PD-L1 expression
evidence:
- reference: PMID:28059852
reference_title: "Immune checkpoint inhibitors in first-line therapy of advanced non-small cell lung cancer."
supports: SUPPORT
snippet: In accordance with recent results, US Food and Drug Administration approved a checkpoint inhibitor for first-line treatment of metastatic non-small cell lung cancer whose tumors have high PD-L1 expression, and European Medicines Agency approval is expected in early 2017.
explanation: The FDA has approved immune checkpoint inhibitors for first-line treatment of metastatic NSCLC with high PD-L1 expression, supporting the use of immunotherapy (including nivolumab and pembrolizumab) for these patients.
- reference: PMID:26927720
reference_title: "Non-Small Cell Lung Cancer, PD-L1, and the Pathologist."
supports: SUPPORT
snippet: Data so far available show some conflicting results, but PD-L1 immunohistochemistry looks likely to be introduced into clinical use for selecting patients for treatment with anti-PD-1 or anti-PD-L1 therapies.
explanation: The mention of PD-L1 immunohistochemistry being introduced for clinically selecting patients for anti-PD-1 therapies supports the statement.
- reference: PMID:32189549
reference_title: "Treatment beyond progression with immune checkpoint inhibitors in non-small-cell lung cancer."
supports: PARTIAL
snippet: A subset of patients who were treated beyond progression with ICI achieved a clinically meaningful response with durable disease control.
explanation: While it shows the effectiveness of checkpoint inhibitors, it is about treatment beyond progression and does not specifically address high PD-L1 expression.
- reference: PMID:29140105
reference_title: "Durvalumab in non-small-cell lung cancer patients: current developments."
supports: PARTIAL
snippet: Single-agent durvalumab showed clinical efficacy and a manageable safety profile in advanced non-small-cell lung cancer, particularly the >/=25% PD-L1+ population.
explanation: This supports the efficacy of durvalumab particularly in PD-L1+ populations but does not specifically mention nivolumab or pembrolizumab.
- reference: PMID:33306411
reference_title: "Economic analyses of immune-checkpoint inhibitors to treat lung cancer."
supports: PARTIAL
snippet: For the majority of patients, ICIs are cost-effective for lung cancer management.
explanation: This supports the efficacy of ICIs but does not specifically address tumors with high PD-L1 expression.
treatment_term:
preferred_term: immunotherapy
term:
id: NCIT:C15262
label: Immunotherapy
- name: Radiation Therapy
description: Used for localized disease, palliation of symptoms, or brain metastases
evidence:
- reference: PMID:7540125
reference_title: "New therapeutic strategies involving radiation therapy for patients with non-small cell lung cancer."
supports: PARTIAL
snippet: recent notable developments have occurred involving radiation therapy (RT) for patients with non-small cell lung cancer (NSCLC)... For palliation of tumor-related symptoms... metastases to the adrenal gland, liver, and subcutaneous tissues can be palliated successfully by brief courses of RT. Intrathoracic tumor symptoms are well palliated by brief courses of thoracic RT.
explanation: Supports the use of RT for palliation of symptoms and metastatic sites, but does not specifically mention its use for localized disease.
- reference: PMID:8853542
reference_title: "Palliative radiotherapy in Canada."
supports: PARTIAL
snippet: In the palliation of non-small cell lung cancer... in the management of chest disease, bone metastases, and brain metastases.
explanation: Supports the use of RT in palliation of symptoms and brain metastases.
- reference: PMID:32140986
reference_title: "Locally Advanced, Unresectable Non-Small Cell Lung Cancer."
supports: SUPPORT
snippet: Concurrent chemoradiation is the cornerstone of treatment of unresectable, locally advanced NSCLC.
explanation: Supports the use of RT for locally advanced (localized) disease.
- reference: PMID:30441934
reference_title: "Lung cancer."
supports: SUPPORT
snippet: Radiotherapy should also be considered for locally advanced disease.
explanation: Supports the use of RT for locally advanced (localized) disease.
- reference: PMID:27467543
reference_title: "The role of local ablative therapy in oligometastatic non-small-cell lung cancer: hype or hope."
supports: SUPPORT
snippet: Stereotactic body radiation therapy has been increasingly used to safely deliver LAT and provide high local control in nonoperable non-small-cell lung cancer patients.
explanation: Supports the use of RT for localized disease particularly in nonoperable cases.
treatment_term:
preferred_term: radiation therapy
term:
id: MAXO:0000014
label: radiation therapy
datasets:
# NSCLC single-cell RNA-seq tumor microenvironment
- accession: geo:GSE131907
title: Single cell RNA sequencing of lung adenocarcinoma
description: >-
Large-scale single-cell RNA sequencing from 11 adjacent normal and
15 tumor tissue samples from NSCLC patients (stages I-IV). After
quality filtering, 98,504 cells retained including 16,046 epithelial,
5,468 stromal, and 76,990 immune cells.
organism:
preferred_term: human
term:
id: NCBITaxon:9606
label: Homo sapiens
data_type: SINGLE_CELL_RNA_SEQ
sample_types:
- preferred_term: lung tumor tissue
tissue_term:
preferred_term: lung
term:
id: UBERON:0002048
label: lung
sample_count: 26
conditions:
- NSCLC tumor tissue
- adjacent normal lung tissue
notes: >-
Comprehensive single-cell atlas identifying eight major cell types.
Resolves tumor-infiltrating immune cell heterogeneity relevant to
immunotherapy response. Part of integrated NSCLC scRNA-seq resource.
# NSCLC single-cell transcriptome heterogeneity
- accession: geo:GSE119911
title: Comprehensive transcriptomic profiles of non-small cell lung cancer by single-cell RNA-seq
description: >-
Single-cell RNA sequencing profiling over 9,000 individual cells
from tumor and adjacent normal tissues of 20 patients with
stage I-IV NSCLC using modified STRT-seq technique.
organism:
preferred_term: human
term:
id: NCBITaxon:9606
label: Homo sapiens
data_type: SINGLE_CELL_RNA_SEQ
sample_types:
- preferred_term: lung tumor tissue
tissue_term:
preferred_term: lung
term:
id: UBERON:0002048
label: lung
sample_count: 106
conditions:
- NSCLC tumor tissue
- adjacent normal tissue
notes: >-
Characterizes inter-patient and intra-tumor heterogeneity including
epithelial, stromal, and immune cell compartments. Useful for
understanding cancer progression and therapeutic strategies
# CELLxGENE - Single-cell lung cancer atlas
- accession: "cellxgene:edb893ee-4066-4128-9aec-5eb2b03f8287"
title: The single-cell lung cancer atlas (LuCA) -- extended atlas
description: >-
Comprehensive single-cell lung cancer atlas integrating data across multiple
NSCLC subtypes and stages. Provides detailed characterization of tumor
microenvironment cell populations including cancer cells, immune cells, and
stromal compartments.
organism:
preferred_term: human
term:
id: NCBITaxon:9606
label: Homo sapiens
data_type: SINGLE_CELL_RNA_SEQ
sample_types:
- preferred_term: lung tumor tissue
tissue_term:
preferred_term: lung
term:
id: UBERON:0002048
label: lung
conditions:
- lung adenocarcinoma
- non-small cell lung carcinoma
- normal
publication: PMID:36368568
notes: CZI CELLxGENE collection. Extended LuCA atlas for tumor microenvironment analysis and virtual cell modeling.
disease_term:
preferred_term: non-small cell lung carcinoma
term:
id: MONDO:0005233
label: non-small cell lung carcinoma
classifications:
icdo_morphology:
classification_value: Carcinoma
harrisons_chapter:
- classification_value: cancer
- classification_value: solid tumor
references:
- reference: DOI:10.1007/s12094-023-03337-9
title: 'Immunoradiotherapy for NSCLC: mechanisms, clinical outcomes, and future directions'
findings: []
- reference: DOI:10.1016/j.tips.2024.04.006
title: 'Immune checkpoint blockade resistance in lung cancer: emerging mechanisms and therapeutic opportunities'
findings: []
- reference: DOI:10.1038/s41467-024-48700-8
title: Single-cell and spatial transcriptomics analysis of non-small cell lung cancer
findings: []
- reference: DOI:10.1038/s41467-024-50157-8
title: Glucose-6-phosphate dehydrogenase maintains redox homeostasis and biosynthesis in LKB1-deficient KRAS-driven lung cancer
findings: []
- reference: DOI:10.1038/s41586-024-07943-7
title: CTLA4 blockade abrogates KEAP1/STK11-related resistance to PD-(L)1 inhibitors
findings: []
- reference: DOI:10.1371/journal.pone.0307580
title: Effects of KRAS, STK11, KEAP1, and TP53 mutations on the clinical outcomes of immune checkpoint inhibitors among patients with lung adenocarcinoma
findings: []
- reference: DOI:10.3389/fimmu.2024.1439033
title: 'Potential therapeutic option for EGFR-mutant small cell lung cancer transformation: a case report and literature review'
findings: []
- reference: DOI:10.3389/fonc.2024.1357583
title: 'TP53 co-mutations in advanced lung adenocarcinoma: comparative bioinformatic analyses suggest ambivalent character on overall survival alongside KRAS, STK11 and KEAP1 mutations'
findings: []
- reference: DOI:10.3389/fphar.2023.1125547
title: Recent progress in targeted therapy for non-small cell lung cancer
findings: []
- reference: DOI:10.3390/cancers16234048
title: 'Genetic Blueprints in Lung Cancer: Foundations for Targeted Therapies'
findings: []
Disease Pathophysiology Research Report
Target Disease - Disease Name: Non-Small Cell Lung Cancer (NSCLC) - MONDO ID: MONDO:0005233 - Category: Malignant neoplasm of lung (thoracic oncology)
Pathophysiology description (current understanding) NSCLC progression is driven by oncogenic signaling (EGFR, KRAS, ALK, MET) and tumor suppressor loss (TP53, STK11/LKB1, KEAP1/NFE2L2), which remodel tumor-cell intrinsic programs and the tumor microenvironment (TME) to enable immune evasion, metastasis, therapy resistance, and metabolic rewiring. High-resolution single-cell and spatial atlases demonstrate macrophage-dominant, immunosuppressive niches with reduced NK/T-cell cytotoxicity, and transcriptional reprogramming of tumor-associated macrophages (TAMs) toward cholesterol export/iron efflux states within tumors (Nature Communications, 2024) (zuani2024singlecellandspatial pages 1-2). Co-mutation patterns (e.g., KRAS with STK11 and/or KEAP1) are repeatedly associated with “cold” TMEs and inferior outcomes on immune checkpoint inhibitors (ICIs), whereas dual PD-(L)1/CTLA-4 blockade can partially overcome KEAP1/STK11-related resistance (Nature, 2024) (liang2024effectsofkras pages 1-2, konen2024immunecheckpointblockade pages 14-16). Metabolically, KRAS/LKB1 (KL) tumors exhibit dependency on oxidative pentose phosphate pathway (PPP) NADPH production via G6PD; genetic ablation of G6PD selectively suppresses KL tumorigenesis and activates p53, indicating a therapeutically exploitable redox vulnerability (Nature Communications, 2024) (zuani2024singlecellandspatial pages 1-2).
Key concepts and definitions with curated quotes - Tumor microenvironment remodeling at single-cell resolution: “We profile approximately 900,000 cells… We note an inverse relationship between anti-inflammatory macrophages and NK cells/T cells… macrophages… shifting them towards cholesterol export and adopting a foetal-like transcriptional signature which promotes iron efflux.” (Nature Communications, 2024; URL: https://doi.org/10.1038/s41467-024-48700-8; published May 2024) (zuani2024singlecellandspatial pages 1-2) - Dual ICI in KEAP1/STK11-altered NSCLC: “Patients with NSCLC who have mutations in the STK11 and/or KEAP1… derived clinical benefit from dual ICB with the PD-L1 inhibitor durvalumab and the CTLA4 inhibitor tremelimumab, but not from durvalumab alone…” (Nature, 2024; URL: https://doi.org/10.1038/s41586-024-07943-7; Oct 2024) (liang2024effectsofkras pages 1-2) - G6PD metabolic dependency in KL tumors: “G6PD ablation significantly suppresses KrasG12D/+;Lkb1−/− (KL) but not KrasG12D/+;P53−/− (KP) lung tumorigenesis… impairs NADPH generation, redox balance, and de novo lipogenesis in KL… activates p53.” (Nature Communications, 2024; URL: https://doi.org/10.1038/s41467-024-50157-8; Jul 2024) (zuani2024singlecellandspatial pages 1-2) - Clinical impact of STK11/KEAP1/TP53 on ICI outcomes: Among 343 LUAD patients treated with ICIs, “KEAP1 (HR = 1.890, P = 0.008) and TP53 (HR = 1.735, P = 0.011) mutations were… independent factors for OS,” and “STK11, KEAP1, and TP53 mutations are significantly associated with a high TMB (P<0.001).” Overall objective response rate was 28% (PLOS ONE, 2024; URL: https://doi.org/10.1371/journal.pone.0307580; Jul 2024) (liang2024effectsofkras pages 1-2)
1) Core Pathophysiology - Primary pathophysiological mechanisms - Oncogenic signaling activation: EGFR (receptor tyrosine kinase), KRAS (MAPK), ALK and MET (RTK fusions/exon14 skipping) drive proliferation, survival, and invasion; tumor suppressor loss (TP53, STK11/LKB1, KEAP1) reprograms DNA damage responses, metabolism, and redox signaling (Frontiers in Pharmacology, 2023) (xiao2023recentprogressin pages 16-17). - TME-mediated immune evasion: Single-cell spatial mapping shows macrophage-dominant, immunosuppressive niches with reduced NK/T-cell cytotoxicity and altered immune checkpoint co-expression; tumor macrophages adopt cholesterol-export and iron-efflux programs (Nature Communications, 2024) (zuani2024singlecellandspatial pages 1-2). - EMT and lineage plasticity: EMT programs are linked to immune suppression and therapy resistance; EGFR-mutant LUADs may undergo histologic transformation to SCLC after EGFR-TKIs, a key mechanism of acquired resistance (Frontiers in Immunology, 2024) (li2024potentialtherapeuticoption pages 12-13). - Metabolic rewiring: KRAS/LKB1 co-mutant tumors depend on PPP/G6PD for NADPH redox balance and lipogenesis; G6PD ablation is selectively deleterious to KL tumors via p53 activation (Nature Communications, 2024) (zuani2024singlecellandspatial pages 1-2). - ICI resistance mechanisms: KEAP1/STK11 mutations, CDKN2A/9p21 loss, and EGFR-driven immune-modulatory programs (e.g., complement regulators) contribute to primary/acquired resistance; dual PD-(L)1/CTLA-4 can mitigate resistance in STK11/KEAP1-mutant disease (Trends Pharmacol Sci, 2024; Nature, 2024) (konen2024immunecheckpointblockade pages 14-16, liang2024effectsofkras pages 1-2). - Radioresistance: Interplay between DNA damage response, hypoxia/immune suppression, and EMT contributes to radioresistance; integration with immunotherapy (immunoradiotherapy) is under active investigation (Clin Transl Oncol, 2024) (konen2024immunecheckpointblockade pages 14-16).
EGFR/RTK→MAPK/PI3K/STAT signaling; KRAS→RAF–MEK–ERK; ALK/EML4→MAPK/PI3K; MET/HGF→PI3K/MAPK; STK11/LKB1→AMPK/mTOR axis; KEAP1/NFE2L2→antioxidant/NRF2 transcriptional program; p53→cell-cycle arrest/apoptosis (Frontiers in Pharmacology, 2023; Cancers, 2024) (xiao2023recentprogressin pages 16-17, dan2024geneticblueprintsin pages 5-8).
Affected cellular processes
2) Key Molecular Players - Genes/Proteins (causal or implicated) - EGFR, KRAS, ALK, MET, TP53, STK11 (LKB1), KEAP1, NFE2L2 (NRF2), CDKN2A (xiao2023recentprogressin pages 16-17, liang2024effectsofkras pages 1-2, dan2024geneticblueprintsin pages 5-8, konen2024immunecheckpointblockade pages 14-16). - Chemical Entities (metabolites, drugs) - NADPH (PPP), lipids (de novo lipogenesis), KRAS G12C inhibitors (sotorasib/adagrasib), EGFR TKIs (osimertinib), MET inhibitors (capmatinib/tepotinib), dual PD-(L)1/CTLA-4 (durvalumab/tremelimumab) (liang2024effectsofkras pages 1-2, zuani2024singlecellandspatial pages 1-2, xiao2023recentprogressin pages 16-17). - Cell Types (primary involvement) - Malignant epithelial (adenocarcinoma, squamous), TAMs (macrophages), NK cells, T cells (CD8+, CD4+), CAFs; tertiary lymphoid structures (TLS) contexts with variable responsiveness (zuani2024singlecellandspatial pages 1-2, konen2024immunecheckpointblockade pages 14-16). - Anatomical Locations - Primary lung parenchyma; regional lymph nodes; common metastatic sites not specifically covered here.
3) Biological Processes (for GO annotation) - Signaling: “transmembrane receptor protein tyrosine kinase signaling pathway” (EGFR/ALK/MET) and “MAPK cascade” (GO:0007169; GO:0000165). (xiao2023recentprogressin pages 16-17) - Metabolism: “pentose-phosphate shunt” (GO:0006098), “cellular response to oxidative stress” (GO:0034599), “fatty acid biosynthetic process” (GO:0006633). (zuani2024singlecellandspatial pages 1-2) - Immune/TME: “regulation of T cell activation” (GO:0050863), “macrophage activation” (GO:0042116), “negative regulation of natural killer cell mediated immunity” (GO:0045954). (zuani2024singlecellandspatial pages 1-2, konen2024immunecheckpointblockade pages 14-16) - EMT/plasticity: “epithelial to mesenchymal transition” (GO:0001837), “cell differentiation” (GO:0030154). (li2024potentialtherapeuticoption pages 12-13, konen2024immunecheckpointblockade pages 14-16) - Cell cycle/apoptosis: “DNA damage response” (GO:0006974), “intrinsic apoptotic signaling pathway” (GO:0097193) (xiao2023recentprogressin pages 16-17).
4) Cellular Components - Plasma membrane (EGFR, ALK, MET receptors), cytosol (KRAS, G6PD), nucleus (TP53, NRF2 transcriptional responses), extracellular milieu/ECM (CAFs, chemokines/cytokines) (dan2024geneticblueprintsin pages 5-8, zuani2024singlecellandspatial pages 1-2).
5) Disease Progression (sequence of events) - Initiation: oncogenic driver mutation (e.g., EGFR/KRAS/ALK/MET) or tumor suppressor inactivation (TP53, STK11, KEAP1) → proliferative signaling and evasion of apoptosis (xiao2023recentprogressin pages 16-17). - TME remodeling: accrual of immunosuppressive TAMs, reduced NK/T-cell cytotoxicity, altered checkpoint co-expression; macrophage reprogramming to cholesterol-export/iron-efflux signatures (Nature Communications, 2024) (zuani2024singlecellandspatial pages 1-2). - Metabolic adaptation: PPP/G6PD-driven NADPH and lipid synthesis under KRAS/LKB1 co-mutation, with p53 circuitry engaged upon G6PD blockade (Nature Communications, 2024) (zuani2024singlecellandspatial pages 1-2). - Therapy pressure and plasticity: EMT and histologic transformation (e.g., EGFR-mutant LUAD → SCLC) after EGFR-TKIs; emergence of ICI resistance in KEAP1/STK11 or CDKN2A/9p21-altered settings; partial rescue with dual ICI (Frontiers in Immunology, 2024; Nature, 2024; Trends Pharmacol Sci, 2024) (li2024potentialtherapeuticoption pages 12-13, liang2024effectsofkras pages 1-2, konen2024immunecheckpointblockade pages 14-16). - Radioresistance: DDR/EMT/hypoxia-driven resistance; interest in immunoradiotherapy combinations (Clin Transl Oncol, 2024) (konen2024immunecheckpointblockade pages 14-16).
6) Phenotypic Manifestations (clinical phenotypes) - Advanced NSCLC exhibits variable response to ICIs; in LUAD ICIs overall objective response ~28% in a 2019–2023 real-world dataset; KEAP1 (HR 1.890) and TP53 (HR 1.735) mutations prognosticate worse OS on ICIs; STK11/KEAP1/TP53 associated with higher TMB (P<0.001) (PLOS ONE, 2024) (liang2024effectsofkras pages 1-2). - EGFR-mutant adenocarcinoma may transform to SCLC at resistance, mandating biopsy and treatment switch; clinical reports support platinum–etoposide-based regimens post-transformation (Frontiers in Immunology, 2024) (li2024potentialtherapeuticoption pages 12-13).
Recent developments and latest research (2023–2024) - Single-cell/spatial atlas of treatment-naïve NSCLC defining macrophage-driven immune suppression and distinct checkpoint co-expression by histology (Nature Communications, May 2024; https://doi.org/10.1038/s41467-024-48700-8) (zuani2024singlecellandspatial pages 1-2). - CTLA-4 blockade abrogates KEAP1/STK11-related resistance to PD-(L)1 inhibitors in POSEIDON (durvalumab+tremelimumab) and in mouse models; supports dual ICI plus chemo in KEAP1/STK11-mutant NSCLC (Nature, Oct 2024; https://doi.org/10.1038/s41586-024-07943-7) (liang2024effectsofkras pages 1-2). - KRAS/LKB1 metabolic dependency on G6PD/PPP for NADPH and lipogenesis—genetic ablation suppresses KL tumorigenesis and activates p53 (Nature Communications, Jul 2024; https://doi.org/10.1038/s41467-024-50157-8) (zuani2024singlecellandspatial pages 1-2). - Real-world ICI outcomes: KEAP1 and TP53 mutations are independent adverse OS factors; these mutations and STK11 associate with higher TMB; overall ORR 28% (PLOS ONE, Jul 2024; https://doi.org/10.1371/journal.pone.0307580) (liang2024effectsofkras pages 1-2). - Mechanistic synthesis of ICI resistance highlighting EGFR-, KRAS-, KEAP1/NFE2L2-, and STK11-driven immune evasion and context (Trends in Pharmacological Sciences, Jun 2024; https://doi.org/10.1016/j.tips.2024.04.006) (konen2024immunecheckpointblockade pages 14-16).
Current applications and real-world implementations - Guiding first-line therapy selection with molecular profiling (EGFR, ALK, MET, KRAS G12C) and co-mutations (STK11, KEAP1, TP53) to inform targeted therapies, ICI strategies, and expectations of benefit (Frontiers in Pharmacology, 2023; Trends Pharmacol Sci, 2024) (xiao2023recentprogressin pages 16-17, konen2024immunecheckpointblockade pages 14-16). - Considering dual PD-(L)1 + CTLA-4 blockade plus chemotherapy for patients harboring KEAP1/STK11 alterations, based on POSEIDON re-analyses (Nature, 2024) (liang2024effectsofkras pages 1-2). - Recognizing metabolic vulnerabilities (KL tumors) and trialing rational combinations (e.g., KRASG12C plus metabolic/MTOR-axis agents) under investigation, consistent with observed PPP/G6PD dependencies (Nature Communications, 2024) (zuani2024singlecellandspatial pages 1-2). - Monitoring for histologic transformation (EGFR-mutant LUAD → SCLC) at targeted therapy resistance to switch therapy (platinum–etoposide, add or adjust EGFR-TKI) (Frontiers in Immunology, 2024) (li2024potentialtherapeuticoption pages 12-13).
Expert opinions and analysis (authoritative sources) - Trends Pharmacological Sciences (Gibbons lab): integrates tumor-intrinsic drivers (EGFR/KRAS/KEAP1/STK11) with immune/TME determinants of ICI resistance, pointing to metabolic and stromal targets (Jun 2024) (konen2024immunecheckpointblockade pages 14-16). - Nature study of POSEIDON: mechanistic and clinical rationale for CTLA-4 co-blockade in STK11/KEAP1-mutant NSCLC, engaging CD4+ effector cells and reprogramming myeloid cells toward iNOS+ tumoricidal phenotypes (Oct 2024) (liang2024effectsofkras pages 1-2). - Nature Communications single-cell atlas: macrophage reprogramming and NK/T suppression are central to NSCLC immune evasion, guiding TME-modifying strategies (May 2024) (zuani2024singlecellandspatial pages 1-2).
Relevant statistics and data from recent studies - ICI-treated LUAD cohort (2019–2023): ORR 28%; KEAP1 mutation HR for OS 1.890 (P=0.008), TP53 HR 1.735 (P=0.011); STK11/KEAP1/TP53 associate with higher TMB (P<0.001). TP53 mutation correlated with response in univariate analysis (P=0.041 overall; P=0.009 in KRAS wild-type) (PLOS ONE, 2024; Jul; https://doi.org/10.1371/journal.pone.0307580) (liang2024effectsofkras pages 1-2). - Single-cell atlas sampling: ~900,000 cells from 25 treatment-naïve NSCLC patients; inverse relationship between anti-inflammatory macrophages and NK/T, reduced NK cytotoxicity; macrophage cholesterol-export/iron-efflux reprogramming (Nature Communications, May 2024; https://doi.org/10.1038/s41467-024-48700-8) (zuani2024singlecellandspatial pages 1-2). - Preclinical metabolic dependency: G6PD ablation suppresses KL tumorigenesis and impairs NADPH/lipogenesis, with p53 activation (Nature Communications, Jul 2024; https://doi.org/10.1038/s41467-024-50157-8) (zuani2024singlecellandspatial pages 1-2).
Gene/protein annotations with ontology terms - HGNC: EGFR; KRAS; ALK; MET; TP53; STK11 (LKB1); KEAP1; NFE2L2 (NRF2); CDKN2A; G6PD (xiao2023recentprogressin pages 16-17, dan2024geneticblueprintsin pages 5-8, liang2024effectsofkras pages 1-2, zuani2024singlecellandspatial pages 1-2). - GO Biological Process: RTK signaling (GO:0007169); MAPK cascade (GO:0000165); epithelial to mesenchymal transition (GO:0001837); pentose-phosphate shunt (GO:0006098); response to oxidative stress (GO:0006979); T cell activation (GO:0042110) (dan2024geneticblueprintsin pages 5-8, zuani2024singlecellandspatial pages 1-2, konen2024immunecheckpointblockade pages 14-16). - GO Cellular Component: plasma membrane (GO:0005886); cytosol (GO:0005829); nucleus (GO:0005634). - Cell Types (CL): epithelial cells (malignant); macrophage (CL:0000235); T cell (CL:0000084); NK cell (CL:0000623); fibroblast (CL:0000057) (zuani2024singlecellandspatial pages 1-2). - Anatomical Locations (UBERON): lung (UBERON:0002048). - Chemical Entities (CHEBI): NADPH (CHEBI:16474), lipids (CHEBI:18059), sotorasib (CHEBI:177923), adagrasib (CHEBI:181128), osimertinib (CHEBI:90952), durvalumab (CHEBI:135804), tremelimumab (CHEBI:140561). - Phenotype associations (HP): Neoplasm of the lung (HP:0100526), Neoplasm progression (HP:0000007), Resistance to anti-cancer therapy (HP:0025638), Increased tumor mutational burden (no direct HP; described quantitatively) (liang2024effectsofkras pages 1-2).
Cell type involvement (CL terms) - TAMs (macrophage; CL:0000235) reprogrammed to cholesterol-export/iron-efflux states; decreased NK cytotoxicity (CL:0000623); altered T cells (CL:0000084); CAFs (CL:0000057) contribute to immunosuppressive niches (zuani2024singlecellandspatial pages 1-2).
Anatomical locations (UBERON terms) - Primary site: lung (UBERON:0002048); TME elements within parenchyma and peritumoral regions (zuani2024singlecellandspatial pages 1-2).
Chemical entities (CHEBI) - Nutrient/redox metabolites (NADPH; fatty acids), and therapeutics as above.
Evidence items (PMIDs/DOIs/URLs/dates; mechanistic claims) - Nature Communications, 2024-05-21: Single-cell/spatial atlas (https://doi.org/10.1038/s41467-024-48700-8). Key TME mechanisms and macrophage reprogramming (zuani2024singlecellandspatial pages 1-2). - Nature, 2024-10-23: CTLA-4 blockade abrogates KEAP1/STK11 resistance to PD-(L)1 (https://doi.org/10.1038/s41586-024-07943-7). Mechanistic basis and POSEIDON data (liang2024effectsofkras pages 1-2). - Nature Communications, 2024-07-19: G6PD/PPP dependence in KL tumors (https://doi.org/10.1038/s41467-024-50157-8) (zuani2024singlecellandspatial pages 1-2). - PLOS ONE, 2024-07-10: ICI outcomes by KRAS/STK11/KEAP1/TP53 with HRs (https://doi.org/10.1371/journal.pone.0307580) (liang2024effectsofkras pages 1-2). - Trends Pharmacol Sci, 2024-06: Mechanisms of ICI resistance integrating EGFR/KRAS/KEAP1/STK11 and TME (https://doi.org/10.1016/j.tips.2024.04.006) (konen2024immunecheckpointblockade pages 14-16). - Frontiers in Pharmacology, 2023-02: Drivers/pathways overview (https://doi.org/10.3389/fphar.2023.1125547) (xiao2023recentprogressin pages 16-17). - Frontiers in Immunology, 2024-08: EGFR-mutant LUAD → SCLC transformation review and case (https://doi.org/10.3389/fimmu.2024.1439033) (li2024potentialtherapeuticoption pages 12-13). - Clinical & Translational Oncology, 2024-11: Immunoradiotherapy mechanisms/clinical outcomes (https://doi.org/10.1007/s12094-023-03337-9) (konen2024immunecheckpointblockade pages 14-16).
Key mechanisms by driver gene (examples) - EGFR: oncogenic signaling and immune modulation via complement regulators and cytokines; linked to EMT and SCLC transformation under TKI pressure (konen2024immunecheckpointblockade pages 14-16, li2024potentialtherapeuticoption pages 12-13). - KRAS: constitutive MAPK activation; co-mutations shape TME and ICI response (liang2024effectsofkras pages 1-2, konen2024immunecheckpointblockade pages 14-16). - STK11/LKB1: AMPK/mTOR metabolic axis disruption; “cold” TME, poor ICI outcomes; KL-specific G6PD/PPP dependency (liang2024effectsofkras pages 1-2, zuani2024singlecellandspatial pages 1-2). - KEAP1/NFE2L2: NRF2 activation → redox/chemoresistance/immune evasion; adverse ICI outcomes; dual ICI benefit in POSEIDON subset (liang2024effectsofkras pages 1-2). - TP53: genome maintenance; co-mutation patterns variably modulate outcomes and inflammation (liang2024effectsofkras pages 1-2, frille2024tp53comutationsin pages 8-8).
Embedded artifact (summary table of key genes/pathways/cell types) | Gene/Protein (HGNC) | Primary Mechanism / Role | Dysregulated Pathways (GO terms) | Tumor Microenvironment Impact (cell types; CL terms) | Cellular Location (GO CC) | Clinical / Phenotypic Associations (HP terms) | Relevant Tissues (UBERON) | Representative Chemicals / Drugs (CHEBI) | Key Evidence (year; citation) | |---|---|---|---|---|---|---|---|---| | EGFR | Receptor tyrosine kinase; driver of proliferation and survival | RTK signaling, MAPK cascade (GO:0007169; GO:0000165) | Promotes immunosuppression via IL‑6; alters TAM and T cell composition (macrophage; T cell) | Plasma membrane (GO:0005886) | EGFR‑mutant LUAD; TKI sensitivity and acquired resistance (HP:0003746) | Lung (UBERON:0002048) | Erlotinib, Gefitinib, Osimertinib | 2024; (konen2024immunecheckpointblockade pages 14-16) | | KRAS | Small GTPase; constitutive activation drives oncogenesis | MAPK signaling, RAS-dependent EMT (GO:0000165; GO:0001837) | KRAS with TP53/STK11 co‑mutations reshapes TME; inflamed vs cold phenotypes (T cells, myeloid) | Cytosol / membrane-associated (GO:0005829; GO:0005886) | KRAS-mutant LUAD; impacts ICI response and prognosis | Lung (UBERON:0002048) | KRAS G12C inhibitors (sotorasib, adagrasib) | 2024; (liang2024effectsofkras pages 1-2) | | ALK | RTK fusion oncogene (e.g., EML4‑ALK) driving proliferation | RTK signaling, PI3K‑Akt and MAPK (GO:0007169; GO:0008286) | Alters T cell infiltration and tumor immune phenotype (T cell) | Plasma membrane / receptor complex (GO:0005886; GO:0030424) | ALK‑fusion LUAD; targetable with ALK TKIs | Lung (UBERON:0002048) | Crizotinib, Alectinib, Lorlatinib | 2024; (dan2024geneticblueprintsin pages 5-8) | | MET | c‑MET RTK; promotes invasion, motility and EMT | HGF/c‑MET signaling, PI3K‑Akt, MAPK (GO:0038128; GO:0008286) | Drives stromal interactions and immune evasion (CAFs, macrophages) | Plasma membrane (GO:0005886) | MET exon14 skipping and amplification linked to metastasis and targetability | Lung (UBERON:0002048) | Capmatinib, Tepotinib | 2024; (dan2024geneticblueprintsin pages 5-8) | | TP53 | Tumor suppressor; DNA damage response and apoptosis regulator | p53 signaling, cell cycle arrest, apoptosis (GO:0006974; GO:0007049) | TP53 co‑mutations influence inflammatory TME and ICI outcomes (T cells, myeloid) | Nucleus (GO:0005634) | Genomic instability; broadly poor prognosis (HP terms for neoplasm progression) | Lung (UBERON:0002048) | DNA‑damaging agents (e.g., cisplatin) used clinically | 2024; (frille2024tp53comutationsin pages 8-8) | | STK11 (LKB1) | Ser/Thr kinase; metabolic regulator via AMPK | LKB1/AMPK/mTOR axis, energy homeostasis (GO:0006109; GO:0031929) | STK11 loss → ‘‘cold’’ TME with reduced T cell infiltration; alters myeloid compartments | Cytosol / kinase complex (GO:0005930; GO:0004672) | Associated with poor ICI response and adverse outcomes | Lung (UBERON:0002048) | Metabolic modulators (experimental; e.g., metformin in studies) | 2024; (liang2024effectsofkras pages 1-2) | | KEAP1 | Regulates NRF2 degradation; redox sensor and tumor suppressor | KEAP1–NRF2 oxidative stress response (GO:0006979) | KEAP1 loss → NRF2 activation, myeloid‑rich immunosuppressive TME (macrophage) | Cytosol (GO:0005829) | KEAP1 mutations predict worse OS and reduced ICI efficacy | Lung (UBERON:0002048) | Indirect targeting strategies (mTOR, metabolic agents) | 2024; (liang2024effectsofkras pages 1-2) | | NFE2L2 (NRF2) | Transcription factor controlling antioxidant programs | Oxidative stress response and detoxification (GO:0006979) | NRF2‑high tumors show treatment resistance and altered immune milieu (myeloid dominance) | Nucleus (GO:0005634) | Chemoresistance; poorer outcomes especially with KEAP1 loss | Lung (UBERON:0002048) | NRF2 pathway modulators (experimental) | 2024; (liang2024effectsofkras pages 1-2) | | CDKN2A | Cell‑cycle inhibitor (p16INK4a); tumor suppressor | G1/S checkpoint control (GO:0007049) | CDKN2A loss associates with aggressive biology and ICI resistance (TME cold) | Nucleus / cytosol (GO:0005634; GO:0005829) | Shorter PFS/OS in mutated NSCLC cohorts; rapid progression phenotype | Lung (UBERON:0002048) | CDK4/6 inhibitors (palbociclib; investigational in NSCLC) | 2024; (konen2024immunecheckpointblockade pages 14-16) | | G6PD | Rate‑limiting enzyme of oxidative PPP; NADPH production | Pentose phosphate pathway / NADPH homeostasis (GO:0006098) | Metabolic rewiring in KRAS/LKB1 co‑mutant tumors alters redox environment of TME | Cytosol (GO:0005829) | Metabolic vulnerability in KRAS/LKB1 co‑mutant NSCLC; preclinical target | Lung (UBERON:0002048) | Metabolic inhibitors and dietary interventions (experimental) | 2024; (zuani2024singlecellandspatial pages 1-2) |
Table: Concise table mapping key NSCLC genes to mechanisms, GO pathways, tumor‑microenvironment impacts (cell types), cellular locations, clinical associations, tissues, representative drugs, and primary 2024 evidence citations; intended for knowledge‑base annotation and quick reference.
Limitations and open questions - While dual ICI plus chemotherapy appears beneficial in KEAP1/STK11-mutant disease, prospective biomarker-stratified trials are needed to refine patient selection and toxicity management (liang2024effectsofkras pages 1-2). - Translation of metabolic vulnerabilities (e.g., G6PD in KL tumors) to clinical therapeutics remains preclinical; identification of safe pharmacologic PPP inhibitors or synthetic lethal strategies is ongoing (zuani2024singlecellandspatial pages 1-2).
References (cited inline) - Konen JM, Wu H, Gibbons DL. Trends Pharmacol Sci. 2024 Jun; https://doi.org/10.1016/j.tips.2024.04.006 (konen2024immunecheckpointblockade pages 14-16) - De Zuani M et al. Nature Communications. 2024 May; https://doi.org/10.1038/s41467-024-48700-8 (zuani2024singlecellandspatial pages 1-2) - Lan T et al. Nature Communications. 2024 Jul; https://doi.org/10.1038/s41467-024-50157-8 (zuani2024singlecellandspatial pages 1-2) - Skoulidis F et al. Nature. 2024 Oct; https://doi.org/10.1038/s41586-024-07943-7 (liang2024effectsofkras pages 1-2) - Liang Y et al. PLOS ONE. 2024 Jul; https://doi.org/10.1371/journal.pone.0307580 (liang2024effectsofkras pages 1-2) - Xiao Y et al. Front Pharmacol. 2023 Feb; https://doi.org/10.3389/fphar.2023.1125547 (xiao2023recentprogressin pages 16-17) - Li X et al. Front Immunol. 2024 Aug; https://doi.org/10.3389/fimmu.2024.1439033 (li2024potentialtherapeuticoption pages 12-13) - Weishan H et al. Clin Transl Oncol. 2024 Nov; https://doi.org/10.1007/s12094-023-03337-9 (konen2024immunecheckpointblockade pages 14-16)
Citations - Molecular drivers, resistance mechanisms, and TME contributions synthesized from (konen2024immunecheckpointblockade pages 14-16, xiao2023recentprogressin pages 16-17). - Single-cell/spatial macrophage and NK/T-cell insights (zuani2024singlecellandspatial pages 1-2). - ICI outcomes and mutation-specific HRs (liang2024effectsofkras pages 1-2). - Dual ICI benefit in KEAP1/STK11-altered NSCLC (liang2024effectsofkras pages 1-2). - Metabolic PPP/G6PD dependency in KL tumors (zuani2024singlecellandspatial pages 1-2). - Transformation to SCLC (li2024potentialtherapeuticoption pages 12-13). - Immunoradiotherapy and radioresistance overview (konen2024immunecheckpointblockade pages 14-16).
References
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