TP53
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.
TP53 is the most commonly mutated gene in cancer (~50% overall, ~80% in TNBC and ovarian). Direct reactivators (eprenetapopt/APR-246) failed in phase 3; Y220C-specific correctors (rezatapopt) are in registrational trials. Indirect strategies exploit G2/M checkpoint dependence (WEE1, ATR, PLK1) and MDM2 inhibition in TP53-wild-type tumours.
- Target · the protein and the cell it sits on
- Drug · antibody, small molecule, cell or radioligand
- Effect · signal, damage or kill
In plain words · 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.
- 1 · What it is
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.
- 2 · What goes wrong in cancer
Transcription factor coordinating cell-cycle arrest, apoptosis, and senescence after DNA damage.
- 3 · How drugs use it
2 products aim at TP53: small molecules. Because the protein is lost rather than overactive, drugs either restore its function or exploit the weakness its loss leaves (synthetic lethality).
Biology
Transcription factor coordinating cell-cycle arrest, apoptosis, and senescence after DNA damage.
- Nearly every cancer type; near-universal in TNBC, high-grade serous ovarian, SCLC
How common it is, by cancer
| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Ovarian cancer | 95% | TP53 mutation (high-grade serous) | cBioPortal (TCGA) | |
| Small-cell lung cancer | >90% | TP53 mutation | RB1 co-loss | Wikipedia |
| Triple-negative breast cancer | 80-85% | TP53 mutation (basal-like) | cBioPortal (TCGA) | |
| Pancreatic ductal adenocarcinoma | 70-75% | TP53 mutation | cBioPortal (TCGA) | |
| Colorectal cancer | 55-60% | TP53 mutation | cBioPortal (TCGA) | |
| Acute myeloid leukaemia | 8-10% | TP53 mutation | Higher in therapy-related AML | cBioPortal (TCGA) |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
Eprenetapopt (APR-246) was a drug meant to refold mutant p53, the most common broken protein in cancer. Its phase 3 in blood cancer failed in 2020.
Selinexor is a first-in-class pill that traps tumour-suppressor proteins inside the nucleus; approved in myeloma, it failed its endometrial cancer test in 2026.
Carrying a cancer mutation is normal; most mutant clones never become cancer. This means blood or tissue tests that look for driver mutations alone will produce false positives, and that the question of what tips a mutant clone into cancer (tissue environment, further hits, immune surveillance) is as important as the mutation itself.
There are not thousands of cancer genes, and any one patient's tumour is driven by only a few of them. That makes targeted sequencing panels sensible, but because most drivers are lost tumour suppressors, drugs exist for only a minority, which is why the same group turned to early detection.
Latest papers
topQuery for this target: (TITLE:"TP53" OR ABSTRACT:"TP53") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about TP53, not a curated reading list.