Tumour suppressors: p53 and RB
Two master brakes. p53 coordinates the response to any emergency; RB holds the door to DNA copying shut. Half of cancers break p53; most of the rest disable it indirectly. RB is bypassed by over-active CDK4/6 or lost outright.
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 fire marshal who is normally kept locked in a cupboard (by MDM2). When alarms sound, the cupboard opens and the marshal stops work, calls repairs, and if the building is beyond saving, orders evacuation (apoptosis) or condemns it (senescence). Cancers either sack the marshal (TP53 mutation) or weld the cupboard shut (MDM2 amplification).
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).
What happens
In plain words, then the glossary entries the stage rests on. Chapter 1, The body's defences: Cancer is not the default.
Two master brakes. p53 coordinates the response to any emergency; RB holds the door to DNA copying shut. Half of cancers break p53; most of the rest disable it indirectly. RB is bypassed by over-active CDK4/6 or lost outright.
The p53 network (guardian of the genome). p53 is the cell's emergency coordinator: DNA damage, oncogene stress or lack of oxygen switch it on, and it then pauses division, orders repairs, or triggers suicide or permanent retirement, while MDM2 keeps it off in healthy cells. About half of cancers mutate p53 outright, and sarcomas, gliomas, melanomas and retinoblastomas silence it instead by amplifying MDM2 or MDM4.
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.
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.
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.
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.
MDM2 is the protein that degrades p53; blocking it reactivates p53 in tumours where the gene is intact, especially the liposarcomas that carry extra copies of MDM2.
A protein that stops cells from self-destructing. Venetoclax removes that protection and has transformed leukaemia treatment.
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.
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.
- AbemaciclibApprovedHR-positive / HER2-negative breast cancerHigh-risk early HR-positive breast cancerHR-positive metastatic breast cancer after CDK4/6 inhibitors
- PalbociclibApprovedHR-positive / HER2-negative breast cancerHER2-positive breast cancer
- RibociclibApprovedHR-positive / HER2-negative breast cancerHigh-risk early HR-positive breast cancer
- DalpiciclibApprovedHR-positive / HER2-negative breast cancer
- TrilaciclibApprovedSmall-cell lung cancer
- AtirmociclibPhase 3
- LerociclibPhase 3
- TQB3616Phase 3
- +1 more at CDK4/6 →
- EprenetapoptNegative
- SelinexorApprovedEndometrial cancerMultiple myelomaDiffuse large B-cell lymphoma
- OSE2101Phase 3
- KRT-232Phase 2
- BrigimadlinPhase 3
- CeralasertibPhase 3
- AzenosertibPhase 3
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.
- 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.
- 2024rctNATALEE: three years of ribociclib after surgery in a broad population of hormone-receptor-positive early breast cancerNew England Journal of Medicinechanged practice
- 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 mutant p53 be reactivated at scale (rezatapopt is the first proof for one mutation)?
- Why do MDM2 inhibitors cause so much marrow toxicity, and can dosing solve it?
- 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 clinicalCDK4-selective inhibitors as the new first-line backbone
If a CDK4-only drug matches CDK4/6 inhibitors on efficacy with less neutropenia, continuous dosing and better adherence could translate into longer control.
- 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.
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
- 2024rctNATALEE: three years of ribociclib after surgery in a broad population of hormone-receptor-positive early breast cancerNew England Journal of Medicinechanged practice
- 2020rctmonarchE: two years of abemaciclib after surgery in high-risk, hormone-receptor-positive early breast cancerJournal of Clinical Oncologychanged 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
- 2017reviewPutting p53 in ContextCell
- 2016observationalBiochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational studyThe Lancet Oncology
- 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
- 2010observationalSubtype-specific genomic alterations define new targets for soft-tissue sarcoma therapyNature Genetics
- 2000reviewThe Hallmarks of Cancer: six capabilities every tumour must acquireCell
- 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 1.6 of 56.