Mitosis and chromosome segregation
A scaffold of microtubules pulls one copy of each chromosome to each daughter, and a checkpoint holds the split until every chromosome is hooked on. Taxanes freeze the scaffold; cells without p53 slip through with the wrong number of chromosomes.
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 tug-of-war where the referee (spindle checkpoint) will not blow the whistle until every player has a grip on the rope. Taxanes glue the rope so nobody can pull; the match never starts and the players eventually collapse. Cells without p53 sneak off the pitch with the wrong number of players, which is how aneuploidy begins.
Chromosomal instability is a library that reshuffles and duplicates random shelves every night. Most rearrangements are useless, some ruin the building, but occasionally one yields a book the librarian needs to survive a new rule, and the mess itself keeps the fire alarms twitching.
What happens
In plain words, then the glossary entries the stage rests on. Chapter 3, Replication and growth machinery: Cancer cells use the same engine as normal cells, only stuck at full throttle.
A scaffold of microtubules pulls one copy of each chromosome to each daughter, and a checkpoint holds the split until every chromosome is hooked on. Taxanes freeze the scaffold; cells without p53 slip through with the wrong number of chromosomes.
Mitosis & the spindle assembly checkpoint. When a cell divides, a scaffold of microtubules (the spindle) pulls one copy of each chromosome to each side. A checkpoint holds the split until every chromosome is hooked on. Taxanes and vinca alkaloids freeze the spindle so the cell is stuck at this checkpoint until it dies.
Chromosomal instability & aneuploidy. Most cancers have the wrong number of chromosomes and keep shuffling them at every division. This chaos fuels evolution and drug resistance, but it also stresses the cell and can trigger immune alarms, a double edge that researchers are trying to exploit.
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.
TP53 is the 'guardian of the genome', broken in half of all cancers. Fixing it directly has so far defeated every attempt, so drugs exploit what its loss makes cancers depend on.
A protein that stops cells from self-destructing. Venetoclax removes that protection and has transformed leukaemia treatment.
A growth receptor that is mutated in some lung cancers and overproduced in others; the first great success of targeted pills.
A growth-signal receptor. Some cancers make far too much of it, and drugs that block it or use it as a docking site have transformed those cancers.
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.
- SelinexorApprovedEndometrial cancerMultiple myelomaDiffuse large B-cell lymphoma
- OSE2101Phase 3
- KRT-232Phase 2
- EprenetapoptNegative
- AfatinibApprovedNon-small-cell lung cancerEGFR-mutated non-small-cell lung cancerHER2-mutant non-small-cell lung cancer
- AmivantamabApprovedNon-small-cell lung cancerEGFR-mutated non-small-cell lung cancerMET exon 14 and MET-amplified non-small-cell lung cancer
- AumolertinibApprovedNon-small-cell lung cancer
- CetuximabApprovedColorectal cancerHead and neck squamous cell carcinomaRecurrent or metastatic head and neck squamous cell carcinoma
- Cetuximab sarotalocanApprovedHead and neck squamous cell carcinoma
- cobas EGFR Mutation Test v2ApprovedNon-small-cell lung cancer
- DacomitinibApprovedNon-small-cell lung cancer
- EncorafenibApprovedColorectal cancerMelanomaNon-small-cell lung cancer
- +42 more at EGFR →
- Trastuzumab emtansineApprovedHER2-positive breast cancerEarly HER2-positive breast cancer
- Disitamab vedotinApprovedGastric & gastro-oesophageal junction cancerBladder & urothelial cancer
- HER2 IHC and ISH companion assays (HercepTest, PATHWAY 4B5, HER2 Dual ISH)ApprovedHER2-positive breast cancerHR-positive / HER2-negative breast cancerGastric & gastro-oesophageal junction cancer
- InetetamabApprovedHER2-positive breast cancer
- MargetuximabApprovedHER2-positive breast cancer
- PertuzumabApprovedHER2-positive breast cancerEarly HER2-positive breast cancer
- SevabertinibApprovedNon-small-cell lung cancerHER2-mutant non-small-cell lung cancer
- TrastuzumabApprovedHER2-positive breast cancerGastric & gastro-oesophageal junction cancerHER2-positive gastric cancer
- +28 more at HER2 →
- Paclitaxel / nab-paclitaxelApprovedTriple-negative breast cancer (TNBC)HR-positive / HER2-negative breast cancerNon-small-cell lung cancer
- DocetaxelApprovedProstate cancerNon-small-cell lung cancerHR-positive / HER2-negative breast cancer
- EribulinApprovedHR-positive / HER2-negative breast cancerTriple-negative breast cancer (TNBC)Sarcomas (soft tissue, bone, GIST)
- VincristineApprovedAcute lymphoblastic leukaemiaDiffuse large B-cell lymphomaHodgkin lymphoma
- Enfortumab vedotinApprovedBladder & urothelial cancerMuscle-invasive and advanced bladder cancer
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 evidenceAttack extrachromosomal DNA, the engine of oncogene amplification
Aggressive glioblastomas, sarcomas and gastric cancers keep amplified cancer genes such as EGFR, MYC, MDM2 and CDK4 on free-floating DNA circles (ecDNA) whose copy number rises and falls quickly, letting the tumour dial resistance up and down. Cells carrying ecDNA depend on CHK1, giving a first drug target.
- 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.
- speculativeresearchDetect tumours changing cell type from RNA in the blood
Some cancers escape treatment by changing into a different kind of cell that the drug no longer affects. Tumour RNA in blood could show this shift months before a biopsy would.
- 2023translationalTRACERx 421: the full-cohort picture of how lung cancer evolves and which subclones drive relapseNature
- 2018rctMURANO: two years of venetoclax plus rituximab versus chemo-immunotherapy in relapsed CLLNew England Journal of Medicinechanged practice
- 2017translationalTRACERx first 100: tracking how lung cancers evolve, and how chromosomal chaos predicts relapseNew England Journal of Medicine
Measured by
Biomarkers, tests and assays in the corpus that read this stage in a patient.
- cobas EGFR Mutation Test v2PCR
- therascreen EGFR RGQ PCR KitPCR
- therascreen KRAS RGQ PCR KitPCR
- therascreen BRAF V600E RGQ PCR KitPCR
- FoundationOne CDxNGS tissue
- FoundationOne Liquid CDxNGS plasma
- Guardant360 CDxNGS plasma
- Oncomine Dx Target TestNGS tissue
- EGFR pharmDxIHC
- HercepTestIHC
- PATHWAY anti-HER2/neu (4B5)IHC
- HER2 IQFISH pharmDx and INFORM HER2 Dual ISHFISH/ISH
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.
- Is chromosomal instability itself a druggable vulnerability (KIF18A) or too heterogeneous?
- Why did Aurora and PLK1 inhibitors show so little activity as single agents?
- being tested at scaleMolecular-class-directed adjuvant therapy in endometrial cancer
Give adjuvant treatment by the tumour's molecular class rather than by stage and grade: nothing for POLE-mutated, immunotherapy for MMRd, chemotherapy plus targeted agents for p53-abnormal, hormones for NSMP.
- early clinicalresearchA biomarker-directed trial of vitamin D after surgery for digestive tract cancers
A Japanese trial found vitamin D supplements did not help everyone after digestive cancer surgery, but appeared to help a subgroup identified by a tumour marker. That subgroup deserves its own trial.
- early clinicalindustryAn open-science consortium on the undruggable drivers, open until a candidate
Companies and public funders would pool money and scientists to crack the hardest cancer proteins, such as MYC and mutant p53, sharing everything openly until there is a real drug candidate, then competing on the final product.
- early clinicalresearchExtend p53 reactivation beyond the Y220C mutation
One faulty version of the p53 guardian protein can now be repaired by a drug that plugs a hole in it. Systematically hunting for similar holes in other faulty versions could help far more patients.
- early clinicalHER2 ADCs as standard for HER2-positive serous endometrial cancer
Serous endometrial cancers often overproduce HER2. Enhertu already works in them; testing HER2 in every p53-abnormal tumour and using the ADC earlier could change outcomes for the worst subtype.
- early clinicalIntercept cancer at the field stage
Whole regions of tissue carry cancer mutations long before a tumour exists. Detecting and treating the field, not the tumour, could prevent cancers rather than cure them.
- early clinicalIs aneuploidy itself a druggable vulnerability?
Most cancers have the wrong number of chromosomes; normal cells do not. If that difference creates a specific weakness, a drug against it would spare normal tissue by definition.
- early clinicalpolicyStop routine endoscopies for non-dysplastic Barrett's oesophagus
People with Barrett's oesophagus without dysplasia have endoscopies every few years, but the BOSS trial found no survival benefit. Redirecting effort to those with dysplasia would save harm and cost.
- early clinicalresearchWhole-body MRI plus blood DNA surveillance for people with Li-Fraumeni syndrome
People with an inherited TP53 mutation face a near-certain lifetime cancer risk. Yearly whole-body MRI catches cancers early; adding blood DNA tests may catch them earlier still.
- preclinical evidenceresearchA synthetic lethality map for every cancer driver in every tissue context
For each cancer-causing mutation, find every gene the cancer cell newly depends on, in every tissue, so that even undruggable drivers get druggable partners.
9 more ideas are linked to this stage's pathways, targets and terms; see the rankings →
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
- 2023translationalTRACERx 421: the full-cohort picture of how lung cancer evolves and which subclones drive relapseNature
- 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
- 2018observationalChromosomal instability drives metastasis through a cytosolic DNA responseNature
- 2018observationalGenome doubling shapes the evolution and prognosis of advanced cancersNature Genetics
- 2018rctMURANO: two years of venetoclax plus rituximab versus chemo-immunotherapy in relapsed CLLNew England Journal of Medicinechanged practice
- 2017translationalTRACERx first 100: tracking how lung cancers evolve, and how chromosomal chaos predicts relapseNew England Journal of Medicine
- 2015basicMartincorena: normal sun-exposed skin is a patchwork of cancer-mutation clonesScience
- 2013reviewCancer genome landscapes: about 140 driver genes, and each tumour needs only a handfulScience
- 2007reviewThe spindle-assembly checkpoint in space and timeNature reviews. Molecular cell biology
- 2000reviewVogelstein, Lane and Levine 2000: surfing the p53 networkNature
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 3.3 of 56.