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Double-strand breaks (HR versus end joining), copying errors (mismatch repair), and single damaged letters (base excision, PARP) each have their crew. Tumours that lost one crew survive on the others, and that dependence is the first widely successful way to drug a lost gene.
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 torn page. The careful archivist (HR) fetches the twin copy from the shelf and transcribes it letter for letter; the hurried clerk (NHEJ) tapes the two halves together, losing a few words. Tumours missing the archivist survive on the clerk, so anything that adds more torn pages (PARP inhibitors, platinum, radiation) buries them.
A spell-checker that runs after every page is typed. Without it, typos pile up, especially in words like 'banana' where it is easy to lose count of the repeats. The garbled words in the resulting proteins read as foreign, so the immune system, once its brakes are released, attacks with unusual vigour.
Potholes on a busy road. Normally a small crew fills them overnight and PARP is the foreman who cones them off. A PARP inhibitor glues the foreman to the pothole; in the morning the traffic (replication) hits him and the road collapses, and only the bridge-building crew (BRCA) could rebuild it.
In plain words, then the glossary entries the stage rests on. Chapter 4, Evading death and repair: To survive the damage they generate and the treatments thrown at them, cancer cells rewire death and repair.
Double-strand breaks (HR versus end joining), copying errors (mismatch repair), and single damaged letters (base excision, PARP) each have their crew. Tumours that lost one crew survive on the others, and that dependence is the first widely successful way to drug a lost gene.
Double-strand break repair: HR versus end joining. A break through both strands of DNA is the most dangerous lesion a cell faces. Two crews compete to fix it: homologous recombination copies the answer from the sister chromosome (accurate, needs BRCA), while end joining simply glues the ends (fast, sloppy). Which crew wins decides whether PARP inhibitors and radiation kill the cell.
Mismatch repair & microsatellite instability. After DNA is copied, a proofreading crew fixes the letters the polymerase got wrong. Lose it and the genome fills with thousands of small errors, especially in repetitive stretches (microsatellites). Those errors make abnormal proteins that the immune system can see, which is why immunotherapy works so well in these cancers.
Base excision repair, PARP & alkylation damage. Tens of thousands of times a day a single DNA letter is oxidised or chemically scarred. A small crew snips it out and PARP marks the nick so it gets sealed. PARP inhibitors do not just switch PARP off; they trap it on the DNA, turning a harmless nick into a lethal break when the cell copies its DNA.
Synthetic lethality: paired dependencies. Two genes are synthetically lethal when losing either alone is fine but losing both kills the cell. Cancers that have already lost one (a tumour suppressor you cannot put back) become uniquely dependent on the other, which you can drug. BRCA and PARP was the first proof; a dozen more pairs are now in trials.
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.
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.
An enzyme that cancers lacking the MTAP gene (about 10-15% of all tumours) depend on more than normal cells do; new inhibitors designed to exploit that difference are in late trials.
A DNA-unwinding enzyme that mismatch-repair-deficient cancers cannot live without; the first WRN inhibitors are in trials as a chemotherapy-free option for MSI-high tumours that fail immunotherapy.
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.
PD-1 is a brake on T cells. Blocking it releases the immune system against the tumour and has cured some previously incurable cancers.
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.
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.
Records tied to this stage that describe resistance, evasion or tolerance. Resistance: how tumours escape each drug class lists the routes class by class.
In advanced prostate cancer the AR-V7 splice variant of the androgen receptor lacks the ligand-binding domain that enzalutamide and abiraterone act on, and its presence predicts resistance. A degrader or N-terminal binder that removes the whole protein, variants included, would still work; AR-V7 is already measurable in circulating tumour cells.
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.
In a minority of men, prostate cancer escapes hormone drugs by becoming a different kind of cell that no longer needs the androgen receptor. By the time a biopsy shows it, the treatment options are almost gone. The genetic changes that allow the switch are detectable years earlier, and nobody is looking for them.
Biomarkers, tests and assays in the corpus that read this stage in a patient.
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.
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.
For some cancers, drugs and radiotherapy can now cure without removing the organ, sparing patients a stoma, a lost voice or a removed bladder. A dedicated programme would run the trials to prove where this is safe.
Anyone with ovarian, pancreatic, metastatic prostate or mismatch-repair-deficient colorectal cancer should be tested for inherited mutations, yet testing rates fall well short. Making it an automatic, opt-out laboratory step triggered by pathology, as reflex mismatch-repair testing already is, would close the gap.
Aspirin roughly halves bowel cancer in Lynch syndrome, and a dose trial is defining how little is needed. Most carriers are still not prescribed it; the task is to fix prescribing.
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.
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.
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.
For each cancer type, agree the set of stains and tests that are always needed, and have the lab run them automatically on diagnosis rather than waiting for someone to ask.
One patient in twenty with pancreatic cancer carries an inherited gene fault, and most have no family history. Guidelines now say test every patient, which finds relatives who carry it too, but the yearly scans that catch cancer at stage I in carriers are still offered only in research programmes. The proposal is to make surveillance follow the test result automatically.
People with Lynch syndrome have a very high lifetime cancer risk from a predictable set of mutations. Vaccinate them against those shared mutations before cancer appears.
55 more ideas are linked to this stage's pathways, targets and terms; see the rankings →
Papers in the corpus tied to this stage's pathways, targets and terms, newest first.
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 4.2 of 56.