Resisting Cell Death Module

Oncology Module resisting_cell_death 1 disorder Pathograph 3

A conserved mechanism module for the third hallmark of cancer (Hanahan & Weinberg): resistance to programmed cell death. Apoptosis is a natural barrier to cancer that is engaged by the physiologic stresses of tumorigenesis, including oncogene-driven hyperproliferation and DNA damage. The mitochondrial (intrinsic) apoptotic program is governed by the BCL-2 family, in which pro-apoptotic effectors (BAX, BAK) and BH3-only sensitizers (BIM, BID, PUMA, NOXA, BAD) are opposed by pro-survival guardians (BCL-2, BCL-XL, MCL-1). The conserved causal chain runs from an apoptosis-evasion lesion (overexpression of pro-survival BCL-2 proteins, loss of pro-apoptotic effectors or of the p53-PUMA/NOXA axis) through a shifted BCL-2-family rheostat that blocks mitochondrial outer-membrane permeabilization and cytochrome c release, to impaired apoptotic execution and the survival of cells that should have died. Individual disorder entries declare conformance via conforms_to, substituting the tumor-type-specific apoptosis-evasion lesion (e.g., t(14;18) BCL2 overexpression in follicular lymphoma, MCL1 amplification, TP53 loss). The shifted rheostat is also the rationale for BH3-mimetic therapy (e.g., venetoclax), which can be captured with target_mechanisms on conforming treatments.

⚙

Pathophysiology Nodes

3 shared nodes are defined in this module.

◉

Cell Types

No cell types are annotated for this module.

⇄

Biological Processes

Notes

This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g., "resisting_cell_death#BCL-2 Family Rheostat Shift Toward Survival"). The module defines the expected pathophysiology structure; conforming nodes in disorder files should include the corresponding biological processes and causal edges, specialized to their tumor context. Key tumor-specific substitutions: follicular lymphoma uses t(14;18)-driven BCL2 overexpression; CLL/AML use BCL-2 or MCL-1 dependence (BH3-mimetic targets); many cancers evade apoptosis through TP53 loss disabling the PUMA/NOXA arm. Key conformance / treatment target: "resisting_cell_death#BCL-2 Family Rheostat Shift Toward Survival".

↗

Used By Disorder Entries

Follicular Lymphoma via BCL2 Overexpression → Apoptosis-Evasion Lesion , Apoptosis Resistance → BCL-2 Family Rheostat Shift Toward Survival

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence-backed metadata.

⚙

Pathophysiology

Apoptosis-Evasion Lesion

trigger

A lesion that biases the cell against apoptosis. Routes include overexpression of pro-survival BCL-2 family members (BCL-2, BCL-XL, MCL-1) via translocation or amplification, loss-of-function of the pro-apoptotic effectors BAX/BAK, silencing of BH3-only sensitizers, or loss of upstream p53 that transactivates PUMA and NOXA. Each lesion raises the apoptotic threshold so that pro-death signals from oncogenic stress fail to trigger cell death.

Negative Regulation of Apoptotic Process GO:0043066 INCREASED

Used by disorders

Follicular Lymphoma as BCL2 Overexpression

Downstream

BCL-2 Family Rheostat Shift Toward Survival

BCL-2 Family Rheostat Shift Toward Survival

central effector

The balance of the BCL-2 family is shifted so that pro-survival members sequester pro-apoptotic effectors and BH3-only proteins, preventing BAX/BAK oligomerization in the mitochondrial outer membrane. With mitochondrial outer-membrane permeabilization blocked, cytochrome c is not released and the apoptosome cannot form. This shifted rheostat is the conserved central node and the molecular target of BH3-mimetic drugs.

Intrinsic Apoptotic Signaling Pathway GO:0097193 DECREASED Release of Cytochrome c from Mitochondria GO:0001836 DECREASED

Used by disorders

Follicular Lymphoma as Apoptosis Resistance

Downstream

Impaired Apoptotic Execution and Cell Survival

Impaired Apoptotic Execution and Cell Survival

consequence

With the intrinsic pathway blocked upstream, effector caspase activation fails and apoptotic execution is impaired. Cells carrying oncogenic and genotoxic stress that should have been culled instead survive and persist, providing a substrate for further malignant evolution and contributing to resistance to chemotherapy and radiotherapy, which act in part by triggering apoptosis.

Apoptotic Process GO:0006915 DECREASED