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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.
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.
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 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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Vaccinate people with BRCA or Lynch mutations against the antigens their future cancers will express, before any cancer exists.
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.
26 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 1.3 of 56.