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Cross-provider research synthesis

RET Rearranged NSCLC

MONDO:0005061 Curated 2026-07-04T00:00:00Z 9 harmonized findings
falcon · 55 citations openscientist · 51 citations
Concordant asserts the finding Partial supports a weaker/qualified form Contradictory conflicts with it Silent does not address it

Harmonized findings

RET-rearranged NSCLC is driven by a somatic chromosomal rearrangement that fuses the 3' RET kinase domain to a 5' partner gene, whose oligomerization domain forces ligand-independent, constitutive activation of the retained RET tyrosine kinase and drives lung adenocarcinogenesis.

UNANIMOUS INTEGRATED
pathophysiologygenetic_factor
ProviderStanceScoreEvidence
falcon CONCORDANT 92% (chromosomal rearrangements) that create constitutively active RET kinase signaling and act as a targetable driver alteration
Falcon states the somatic fusion creates constitutively active RET kinase signaling as the targetable driver.
DOI:10.1007/s40265-024-02040-5
openscientist CONCORDANT 95% Gain of function — the partner gene's coiled-coil/oligomerization domain replaces RET's extracellular ligand-binding domain, forcing constitutive, ligand-independent dimerization and autophosphorylation of the retained intracellular kinase domain
OpenScientist adds the precise gain-of-function mechanism (partner oligomerization domain forcing ligand-independent dimerization of the retained kinase).
PMID:40102258

KIF5B-RET is the dominant fusion partner, followed by CCDC6-RET and NCOA4-RET, all arising predominantly from intrachromosomal inversions of chromosome 10.

UNANIMOUS INTEGRATED
genetic_factor
ProviderStanceScoreEvidence
falcon CONCORDANT 85% often dominant; e.g., 40–70% in one review; 70–90% in another; 59.4% in a China real‑world cohort
Falcon reports KIF5B-RET as the dominant partner with wide cohort-dependent frequency ranges, plus CCDC6-RET and NCOA4-RET.
DOI:10.1093/oncolo/oyac264
openscientist CONCORDANT 90% KIF5B (46.8%) was the most common fusion partner followed by CCDC6 (28.3%) and NCOA4 (13.8%) in RET+ solid tumors. KIF5B-RET was the dominant fusion variant in RET+ NSCLC
OpenScientist gives concordant partner ranking with quantitative frequencies for KIF5B, CCDC6, and NCOA4.
PMID:37516008

The RET fusion kinase signals through multiple canonical RTK effector cascades — RAS-MAPK, PI3K-AKT, and JAK-STAT, together with PLCgamma — to drive proliferation, survival, and migration.

UNANIMOUS INTEGRATED
pathophysiologygene_function
ProviderStanceScoreEvidence
falcon CONCORDANT 88% Spitaleri et al. detail RET phosphotyrosine sites linked to specific pathways (e.g., Y1062 to Ras/MAPK and PI3K/AKT; Y752/Y928 to STAT3)
Falcon maps RET phosphotyrosine docking sites to RAS/MAPK, PI3K/AKT, and STAT3 signaling.
DOI:10.3390/cancers16162877
openscientist CONCORDANT 90% This activated complex regulates a number of downstream signaling cascades (PLCγ, MAPK, and PI3K) that control proliferation, migration, renewal, and apoptosis
OpenScientist lists the same effector cascades (PLCgamma, MAPK, PI3K) governing proliferation and migration.
PMID:24022366

RET fusions comprise roughly 1-2% of NSCLC and are enriched in younger, never/light-smoking patients with adenocarcinoma histology and a female predominance.

UNANIMOUS INTEGRATED
epidemiologyphenotype
ProviderStanceScoreEvidence
openscientist CONCORDANT 95% affecting approximately 1–2% of NSCLC patients, predominantly presenting as lung adenocarcinoma in younger, female, never-smoking individuals
OpenScientist gives the prevalence and full demographic enrichment (median age 58, 57% female, 60.8% never/light smokers).
PMID:40544107, PMID:41707338
falcon CONCORDANT 75% younger age, adenocarcinoma histology, low tobacco exposure, and elevated risk of brain metastases
Falcon reports the same demographic enrichment and independently estimates ~1-2% prevalence, but frames age around a median of 63 years (versus OpenScientist's 58) — a minor quantitative difference, not a conflict.
DOI:10.1093/oncolo/oyac264

RET-rearranged NSCLC has a strong propensity for CNS/brain metastasis, present in a substantial fraction at diagnosis and accumulating over the disease course, making brain involvement a common pattern of treatment failure.

UNANIMOUS INTEGRATED
phenotype
ProviderStanceScoreEvidence
falcon CONCORDANT 85% About 25% of patients with stage IV RET fusion-positive NSCLC have brain metastases at diagnosis
Falcon quantifies baseline CNS burden (~25% at stage IV diagnosis; 46% lifetime prevalence elsewhere in the report).
DOI:10.3390/cancers16010031
openscientist CONCORDANT 80% Notable propensity for CNS involvement; up to 25-30% during disease course. Brain metastases are a common pattern of treatment failure
OpenScientist agrees CNS involvement reaches 25-30% over the course and drives treatment failure, though it reports a lower baseline brain-metastasis fraction (6.7% as a metastatic site) — a quantitative nuance.
PMID:39563271

First-line selpercatinib markedly improves progression-free survival versus platinum-based chemotherapy with or without pembrolizumab in advanced RET fusion-positive NSCLC (LIBRETTO-431; median PFS 24.8 vs 11.2 months).

UNANIMOUS INTEGRATED
treatmentprognosis
ProviderStanceScoreEvidence
falcon CONCORDANT 95% Treatment with selpercatinib led to significantly longer progression‑free survival than platinum‑based chemotherapy with or without pembrolizumab among patients with advanced RET fusion‑positive NSCLC
Falcon quotes the LIBRETTO-431 NEJM conclusion, with median PFS 24.8 vs 11.2 months and ORR 84% vs 65%.
DOI:10.1056/NEJMoa2309457
openscientist CONCORDANT 95% median progression-free survival was 24.8 months (95% CI, 16.9 to not estimable) with selpercatinib and 11.2 months (95% CI, 8.8 to 16.8) with control treatment (hazard ratio for progression or death, 0.46; 95% CI, 0.31 to 0.70; P<0.001)
OpenScientist reports the identical LIBRETTO-431 PFS result with the full hazard ratio and confidence intervals.
PMID:37870973

RET fusion-positive NSCLC has an immune-cold tumor microenvironment (low tumor mutational burden, low PD-L1, poor T-cell infiltration), which underlies the limited benefit of immune checkpoint therapy.

UNANIMOUS INTEGRATED
pathophysiologytreatment
ProviderStanceScoreEvidence
falcon CONCORDANT 82% Cohort summaries describe generally low PD-L1 expression, consistent with limited benefit from immunotherapy in many RET-driven tumors
Falcon links low PD-L1/TMB to limited immunotherapy benefit (IMMUNOTARGET ORR 6% cited elsewhere).
DOI:10.3390/cancers16010031
openscientist CONCORDANT 90% immunotherapy alone shows minimal benefit due to the characteristically immune-cold tumor microenvironment (low TMB, poor T-cell infiltration)
OpenScientist frames the immune-cold phenotype (low TMB, poor T-cell infiltration) as the basis for minimal immunotherapy benefit.
PMID:35838839, PMID:41424613

Acquired resistance to selective RET inhibitors arises through on-target RET G810 solvent-front mutations and off-target bypass pathways (notably MET amplification).

UNANIMOUS INTEGRATED
pathophysiologygenetic_factortreatment
ProviderStanceScoreEvidence
falcon CONCORDANT 85% solvent‑front mutations at RET G810 (G810C/S/R)
Falcon identifies RET G810 solvent-front mutations plus off-target bypass (MET amplification, EGFR/AXL, FGFR) as resistance mechanisms.
DOI:10.1093/oncolo/oyac264
openscientist CONCORDANT 90% Analysis of circulating tumor DNA revealed emergence of RET G810R, G810S, and G810C mutations in the RET solvent front before the emergence of clinical resistance
OpenScientist details the same G810 solvent-front mutations (detected by ctDNA) alongside MET/KRAS amplification bypass.
PMID:31988000, PMID:33007380

Wild-type RET is a receptor tyrosine kinase required for normal development of the kidneys, ureters, and peripheral and enteric nervous systems, distinct from its oncogenic fusion activity.

SINGLE LEAD
gene_function
ProviderStanceScoreEvidence
openscientist CONCORDANT 90% a receptor tyrosine kinase essential for normal development of the kidneys, ureters, peripheral and enteric nervous systems
OpenScientist describes the physiologic developmental role of normal RET as background to the fusion-driven disease.
PMID:24022366, PMID:17934909
falcon SILENT —
Falcon's report focuses on the oncogenic fusion and treatment landscape and does not describe the normal developmental function of wild-type RET.

Narrative

Overview

Both providers frame RET-rearranged NSCLC as a rare (~1-2%) but highly actionable fusion-driven lung adenocarcinoma subtype, enriched in younger, female, never/light-smoking patients, with constitutive RET kinase signaling, selective RET tyrosine kinase inhibition (selpercatinib, pralsetinib), frequent CNS metastasis, an immune-cold microenvironment, and acquired resistance as the major curated concepts.

Agreement

Both identify RET-rearranged NSCLC as a fusion-driven adenocarcinoma with KIF5B-RET as the dominant partner (followed by CCDC6 and NCOA4), constitutive ligand-independent RET signaling through RAS-MAPK, PI3K-AKT, JAK-STAT, and PLCgamma, and strong first-line benefit from selpercatinib (LIBRETTO-431 PFS 24.8 vs 11.2 months). They converge on the immune-cold/low-TMB microenvironment with limited immunotherapy benefit, the CNS-metastasis propensity, and resistance via on-target RET G810 solvent-front mutations plus MET/bypass signaling.

Divergence

Falcon emphasized the selective RET inhibitor treatment landscape, diagnostic modality comparison (RNA-based NGS preferred), first-line selpercatinib and real-world RET-TKI cohorts, and a KIF5B-RET transgenic mouse model. OpenScientist added deeper molecular and resistance detail: RET protein-domain and structural biology, co-occurring TP53/CDKN2A alterations, an expanded bypass-resistance catalog (MET/KRAS amplification, AXL/IGF-1R, SMARCA4 loss), next-generation RET inhibitors, and the physiologic role of wild-type RET. Quantitative differences are minor (median age 63 vs 58 years; baseline brain-metastasis fraction ~25% vs 6.7%) rather than contradictions.

Integration

Integrated into kb/disorders/RET_Rearranged_NSCLC.yaml: the driver mechanism and fusion-partner spectrum, the multi-pathway effector signaling, the epidemiology/demographic enrichment, the CNS-metastasis phenotype, the immune-cold microenvironment and weak immunotherapy signal, the RET inhibitor resistance node (G810R/S/C plus MET/KRAS bypass), and the first-line selpercatinib LIBRETTO-431 evidence.

Not integrated (leads)

Next-generation investigational RET inhibitors, experimental RET/SRC and RET/MET combination strategies, fine-grained adverse-event management, and the contextual normal-RET developmental biology were retained as research leads rather than promoted to curated disease mechanisms.

Cross-provider synthesis of two independent deep-research reports: falcon (treatment/diagnostics-focused) and openscientist (comprehensive, 15-domain, richer molecular/resistance detail). No direct contradictions were found; the divergence is coverage/recency plus minor quantitative discrepancies (median age, baseline brain-metastasis fraction). best_matching_text values are verbatim excerpts from the cited report files; literature evidence snippets were intentionally left unpopulated pending fetch-reference verification of the underlying PMIDs/DOIs.