DNA damage checkpoints
Before a cell copies or divides, sensors check the DNA. Damage halts the cycle until repair crews finish; severe damage triggers suicide. Cancers cut the sensors and, in doing so, become dependent on the few repair routes they have left.
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 checkpoint at a border: p53 is the inspector who halts traffic when something looks wrong, MDM2 is the manager who keeps sending the inspector home, RB is the barrier arm, and CDK4/6 is the motor that lifts it. Cancers bribe the inspector (TP53 mutation) or hot-wire the motor (cyclin D amplification).
Two repair crews for a road: PARP fixes potholes, BRCA rebuilds collapsed bridges. A town that has lost its bridge crew (BRCA mutation) survives as long as potholes are fixed before they become bridge collapses. Block the pothole crew (PARP inhibitor) and the bridges fall.
A photocopier running at triple speed with the paper-jam sensor removed. It keeps working only because a technician (ATR/CHK1/WEE1) constantly clears jams. Remove the technician and it destroys itself.
What happens
In plain words, then the glossary entries the stage rests on. Chapter 1, The body's defences: Cancer is not the default.
Before a cell copies or divides, sensors check the DNA. Damage halts the cycle until repair crews finish; severe damage triggers suicide. Cancers cut the sensors and, in doing so, become dependent on the few repair routes they have left.
p53 / RB / cell-cycle checkpoint. The p53 and RB checkpoints are the cell's brakes. p53 senses damage and stops the cell from copying itself; RB holds the cell at the G1 gate until CDK4/6 unlocks it. Cancers cut these brakes.
DNA damage response & homologous recombination. The DNA damage response is the cell's set of repair crews. Single-strand breaks are patched by PARP; double-strand breaks by BRCA-dependent homologous recombination. Lose one crew and the cell survives; lose both and it dies. That is how PARP inhibitors work.
DNA replication stress. Cancers copy their DNA too fast and with broken checkpoints, so replication forks stall and collapse. They survive only by leaning on emergency repair kinases such as ATR, CHK1, and WEE1, which is why blocking those kinases can be selectively lethal.
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.
PARP is a DNA repair enzyme. Cancers that have already lost one repair system (BRCA) die when this second one is blocked; healthy cells survive.
DNA repair genes. Inheriting a broken copy raises breast and ovarian cancer risk, but tumours that lose them become uniquely vulnerable to PARP inhibitors and platinum.
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.
ATR is a DNA-damage alarm kinase. Blocking it makes tumours with broken repair systems collapse under their own replication stress.
A checkpoint kinase that gives cells time to fix DNA before dividing. Removing it forces damaged cancer cells into a fatal division.
KRAS is the most commonly mutated cancer gene, called 'undruggable' for 40 years until 2021.
CDK4/6 is the engine that pushes a cell to copy its DNA. Blocking it alongside hormone therapy roughly doubled the time hormone-driven breast cancer stays controlled.
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.
- NiraparibApprovedOvarian cancerProstate cancerHigh-grade serous ovarian cancer
- OlaparibApprovedOvarian cancerTriple-negative breast cancer (TNBC)HR-positive / HER2-negative breast cancer
- TalazoparibApprovedTriple-negative breast cancer (TNBC)HR-positive / HER2-negative breast cancerProstate cancer
- BRACAnalysis CDxApprovedOvarian cancerHR-positive / HER2-negative breast cancerTriple-negative breast cancer (TNBC)
- myChoice CDxApprovedOvarian cancer
- RucaparibApprovedOvarian cancerProstate cancerHigh-grade serous ovarian cancer
- SaruparibPhase 3
- PalacaparibPhase 2
- +1 more at PARP →
- SelinexorApprovedEndometrial cancerMultiple myelomaDiffuse large B-cell lymphoma
- OSE2101Phase 3
- KRT-232Phase 2
- EprenetapoptNegative
- CeralasertibPhase 3
- AzenosertibPhase 3
- AdagrasibApprovedNon-small-cell lung cancerColorectal cancerPancreatic ductal adenocarcinoma
- Avutometinib + defactinibApprovedOvarian cancerLow-grade serous ovarian cancer
- DaraxonrasibApprovedPancreatic ductal adenocarcinomaMetastatic pancreatic ductal adenocarcinomaKRAS G12C-mutant pancreatic ductal adenocarcinoma
- FulzerasibApprovedNon-small-cell lung cancer
- GarsorasibApprovedNon-small-cell lung cancerKRAS G12C-mutant non-small-cell lung cancer
- GlecirasibApprovedNon-small-cell lung cancerKRAS G12C-mutant non-small-cell lung cancer
- Guardant360 CDxApprovedNon-small-cell lung cancerHR-positive / HER2-negative breast cancer
- Resolution ctDx FIRSTApprovedNon-small-cell lung cancer
- +16 more at KRAS →
- AbemaciclibApprovedHR-positive / HER2-negative breast cancerHigh-risk early HR-positive breast cancerHR-positive metastatic breast cancer after CDK4/6 inhibitors
- DalpiciclibApprovedHR-positive / HER2-negative breast cancer
- PalbociclibApprovedHR-positive / HER2-negative breast cancerHER2-positive breast cancer
- RibociclibApprovedHR-positive / HER2-negative breast cancerHigh-risk early HR-positive breast cancer
- TrilaciclibApprovedSmall-cell lung cancer
- AtirmociclibPhase 3
- LerociclibPhase 3
- TQB3616Phase 3
- +1 more at CDK4/6 →
How tumours escape
Records tied to this stage that describe resistance, evasion or tolerance. The resistance atlas lists the routes class by class.
- 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 evidenceresearchTurn off the error-prone repair that manufactures resistance mutations
Under treatment stress, cancer cells switch on sloppy DNA copying that generates the mutations they need to survive. Blocking that machinery could stop resistance being invented.
- 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.
- 2021rctOlympiA: a year of olaparib after surgery for BRCA-mutated, high-risk early breast cancerNew England Journal of Medicinechanged practice
- 2018rctSOLO-1: two years of olaparib maintenance after first-line chemotherapy for BRCA-mutated ovarian cancerNew England Journal of Medicinechanged practice
- 2006basicBao 2006: glioma stem cells resist radiotherapy by activating the DNA damage responseNature
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.
- How wide is the therapeutic window for ATR, WEE1 and CHK1 inhibitors given that normal dividing tissue uses the same checkpoints?
- Can checkpoint status be read from a routine biopsy or blood test?
- being tested at scaleresearchA bone drug to prevent breast cancer in BRCA1 carriers
BRCA1 breast cancers seem to grow from cells driven by the RANK signal. Denosumab blocks it and is already used for bone. A trial is testing whether it prevents these cancers.
- 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.
- being tested at scalepolicyOffer everyone at 30 a test for the cancer genes that matter
Most people with BRCA or Lynch mutations do not know until they get cancer. Testing everyone once for a short list of high-impact genes would find them in time to prevent it.
- being tested at scalepolicyPopulation germline screening for hereditary cancer genes with cascade testing
Most people carrying a high-risk cancer gene do not know it until someone in the family gets cancer. Offer testing to all adults so carriers can be protected before that happens.
- 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 clinicalresearchAttack the backup copy when a tumour has lost the original gene
Tumours often lose one of a pair of near-identical genes. They then depend entirely on the remaining copy, which a drug can block, killing only the cancer.
- early clinicalCancer interception vaccines for high-risk carriers
Vaccinate people with BRCA or Lynch mutations against the antigens their future cancers will express, before any cancer exists.
- 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 clinicalclinicGo back to families of women who died of ovarian cancer and offer BRCA testing
Women who died of ovarian cancer without ever having BRCA testing leave relatives who are otherwise unreachable. Retesting archived tumour tissue and contacting families, piloted on 2,000 cases from the past 15 years, would find carriers before they develop cancer; US pilots show it is feasible and ethically acceptable.
22 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.
- 2022reviewHallmarks of DNA replication stressMolecular cell
- 2021rctOlympiA: a year of olaparib after surgery for BRCA-mutated, high-risk early breast cancerNew England Journal of Medicinechanged practice
- 2019rctPAOLA-1: olaparib added to bevacizumab maintenance in newly diagnosed ovarian cancer, with benefit confined to HRD-positive tumoursNew England Journal of Medicinechanged practice
- 2018rctSOLO-1: two years of olaparib maintenance after first-line chemotherapy for BRCA-mutated ovarian cancerNew England Journal of Medicinechanged practice
- 2017basicDefining a Cancer Dependency Map: which genes each cancer cell line cannot live withoutCell
- 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
- 2010observationalPROSE consortium: preventive surgery lowers cancer and death in BRCA1 and BRCA2 carriersJAMAchanged practice
- 2006basicBao 2006: glioma stem cells resist radiotherapy by activating the DNA damage responseNature
- 2000reviewThe Hallmarks of Cancer: six capabilities every tumour must acquireCell
- 2000reviewVogelstein, Lane and Levine 2000: surfing the p53 networkNature
- 1999reviewSherr and Roberts 1999: CDK inhibitors as regulators of the G1 phaseGenes and Development
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 1.3 of 56.