Apoptosis: the self-destruct switch
Every cell carries a demolition kit. Internal alarms (damage, oncogene stress) or external orders (from immune cells) set it off. Cancer cells wire the kit shut with proteins such as BCL-2, and venetoclax proved that cutting that wire can put leukaemia into remission.
Diagram
Pick a product above a diagram to see the nodes it hits and the escape routes below the block. Hover or tap any node or arrow for what it is; every node opens its target, glossary entry or the pathway page. Violet boxes are druggable targets.
A dam (mitochondrial membrane) held by guards (BCL-2, MCL-1) against demolition crews (BAX/BAK). Cancer hires extra guards. Venetoclax fires the BCL-2 guards, and the dam breaks.
A doorbell wired to a self-destruct switch: immune cells ring it. Some tumours rip out the doorbell (FAS loss), some stuff the wiring with insulation (c-FLIP), and some install a second doorbell that rings nowhere (decoy receptors).
What happens
In plain words, then the glossary entries the stage rests on. Chapter 1, The body's defences: Cancer is not the default.
Every cell carries a demolition kit. Internal alarms (damage, oncogene stress) or external orders (from immune cells) set it off. Cancer cells wire the kit shut with proteins such as BCL-2, and venetoclax proved that cutting that wire can put leukaemia into remission.
Intrinsic apoptosis (BCL-2 family). Intrinsic apoptosis is the cell's self-destruct switch. BCL-2 holds it shut; BAX and BAK pull it open. Venetoclax pries BCL-2 off so the switch can fire.
Extrinsic apoptosis (death receptors). Immune cells kill by touch: they present FAS ligand or TRAIL to a target cell, whose death receptors then trigger self-destruction from the outside in. Tumours cut this wire by deleting the receptors or over-producing decoys and blockers.
The molecular players
The proteins and genes at this stage, with their role and how many products act on each. Listed players come from the atlas; drawn players sit as nodes in the diagrams above.
A protein that stops cells from self-destructing. Venetoclax removes that protection and has transformed leukaemia treatment.
CD3 is the switch on every T cell. Bispecific drugs grab it with one arm and the tumour with the other, forcing the T cell to attack.
Where medicines act
Products grouped by the node they hit, most advanced first, with the cancers an approved product is linked to. Pick one above the diagram to see it light up.
- BlinatumomabApprovedAcute lymphoblastic leukaemiaStandard-risk B-cell acute lymphoblastic leukaemia in childrenRelapsed and refractory acute lymphoblastic leukaemia in children
- CatumaxomabApprovedOvarian cancerGastric & gastro-oesophageal junction cancerPancreatic ductal adenocarcinoma
- ElranatamabApprovedMultiple myelomaRelapsed or refractory multiple myeloma
- EpcoritamabApprovedDiffuse large B-cell lymphoma
- GlofitamabApprovedDiffuse large B-cell lymphoma
- LinvoseltamabApprovedMultiple myelomaRelapsed or refractory multiple myeloma
- MosunetuzumabApprovedDiffuse large B-cell lymphoma
- OdronextamabApprovedDiffuse large B-cell lymphoma
- +16 more at CD3 →
How tumours escape
Records tied to this stage that describe resistance, evasion or tolerance. The resistance atlas lists the routes class by class.
- early clinicalBTK degraders to pre-empt resistance in frontline CLL
If destroying BTK works when every inhibitor has failed, using it first might stop resistance from ever emerging.
- preclinical evidenceresearchClear the zombie cells left behind by chemotherapy and radiotherapy
Treatment leaves behind damaged cells that stop dividing but do not die, and they release signals that help surviving cancer cells regrow. Removing them could reduce relapse.
- preclinical evidenceOne-two punch: clear senescent cells after chemotherapy
Chemotherapy leaves behind senescent cells that inflame tissues and help tumours relapse. A short course of senolytic drugs afterwards might reduce relapse and long-term side effects at once.
- 2018rctMURANO: two years of venetoclax plus rituximab versus chemo-immunotherapy in relapsed CLLNew England Journal of Medicinechanged practice
Measured by
Biomarkers, tests and assays in the corpus that read this stage in a patient.
Open questions
What is not known at this stage: the atlas's own questions, the bottlenecks it bears on, and the ideas in the corpus that try to answer them.
- Can MCL-1 and BCL-XL be drugged without heart and platelet toxicity?
- Does BH3 profiling of a patient's cells predict which BH3 mimetic will work?
Key evidence
Papers in the corpus tied to this stage's pathways, targets and terms, newest first.
- 2025rctAMPLIFY: fixed-duration acalabrutinib plus venetoclax, with or without obinutuzumab, versus chemo-immunotherapy in fit CLL patientsNew England Journal of Medicinechanged practice
- 2020rctVIALE-A: venetoclax plus azacitidine for older adults with acute myeloid leukaemia who cannot have intensive chemotherapyNew England Journal of Medicinechanged practice
- 2019rctCLL14: one year of venetoclax plus obinutuzumab instead of chemo-immunotherapy in older, less fit CLL patientsNew England Journal of Medicinechanged practice
- 2018rctMURANO: two years of venetoclax plus rituximab versus chemo-immunotherapy in relapsed CLLNew England Journal of Medicinechanged practice
- 2015reviewTargeting the extrinsic apoptotic pathway in cancer: lessons learned and future directionsJournal of Clinical Investigation
- 2000reviewThe Hallmarks of Cancer: six capabilities every tumour must acquireCell
src/data/mechanics-atlas.ts). Players, medicines, escape routes, tests, ideas and papers are resolved from the knowledge graph at build time through the stage's pathways, targets and terms, so every item here has its own page and sources. Where a section is missing, the corpus has no record tied to the stage yet. Nothing here is medical advice; see about and methodology. Stage 1.4 of 56.