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. This dossier gathers the 2 products (1 approved), 2 trials, 14 pathways and 2 resistance routes in the corpus that involve it, with external identifiers so it can be joined to UniProt, ChEMBL, Open Targets and the rest of biology.
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
Elsewhere: identifiers and databases
Built from HGNC, Ensembl, UniProt and ChEMBL idsHow common it is, by cancer
Full matrix →| 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.
Mutation hotspots and which drugs address them
| Residue | Kind | How common | What it does | Addressed by | Defeats | Source |
|---|---|---|---|---|---|---|
| R175H 175 | Loss of function | not sourced | Structural (conformational) hotspot: unfolds the DNA-binding domain. Target of reactivator programmes, none approved. | none in corpus | — | Olivier et al., Cold Spring Harb Perspect Biol 2010 |
| Y220C 220 | Loss of function | About 1.5% of TP53 mutations | Creates a surface crevice that small molecules can bind to re-stabilise the fold; the only p53 allele with a residue-specific reactivator in clinical trials. | none in corpus | — | Olivier et al., Cold Spring Harb Perspect Biol 2010 |
| R248Q / R248W 248 | Loss of function | not sourced | DNA-contact hotspot; R248Q also gains oncogenic functions in several models. | none in corpus | — | Olivier et al., Cold Spring Harb Perspect Biol 2010 |
| R273C / R273H 273 | Loss of function | not sourced | DNA-contact hotspot; among the most frequent alleles in every tumour type. | none in corpus | — | Olivier et al., Cold Spring Harb Perspect Biol 2010 |
| G245S / R249S / R282W 282 | Loss of function | not sourced | Further structural hotspots; R249S is the aflatoxin signature in liver cancer. | none in corpus | — | Olivier et al., Cold Spring Harb Perspect Biol 2010 |
Frequencies are quoted from the source on each row; a blank means no figure was sourced, not that it is rare. Domain boundaries are approximate. Sources for the map: TP53 Database (NCI, formerly IARC) · Cancer Hotspots (MSK) · COSMIC: TP53.
Products by modality and phase
Browse products →| Modality | Approved | Withdrawn or failed |
|---|---|---|
| Small molecule 2 |
Trials
Evidence ranking →| Trial | Phase | Status | Setting | Result | Products |
|---|---|---|---|---|---|
| XPORT-EC-042 / ENGOT-EN20 / GOG-3083 NCT05611931 | 3 | Negative | TP53-wild-type advanced or recurrent endometrial cancer after response to platinum: maintenance selinexor vs placebo | Primary PFS endpoint not met; mPFS 12.75 vs 7.43 months (mITT) not significant. | |
| PORTEC-3 NCT00411138 | 3 | Positive | High-risk early or stage III endometrial cancer after surgery: chemoradiation + 4 cycles chemotherapy vs pelvic radiotherapy alone | 5-year OS 81.4% vs 76.1% (HR 0.70); benefit concentrated in p53-abnormal disease. |
Resistance routes that involve this target
Unaddressed routes →Conversion to small-cell lung cancer (RB1/TP53 co-loss) or squamous histology; EGFR mutation persists but the cell no longer depends on it.
- Re-biopsy at progression; platinum-etoposide for SCLC transformation
RB1/TP53 loss enables transdifferentiation; AR-indifferent, DLL3-positive, PSMA-negative.
- Platinum-etoposide; DLL3 engagers (tarlatamab) and B7-H3 ADCs in trials
Pathways where it is a node
Pathway-to-drug matrix →- Cellular senescenceNode: p53 → p21 · 2 druggable nodes
Damaged cells can stop dividing permanently instead of dying. That protects against cancer at first, but senescent cells linger, secrete inflammatory signals, and after chemotherapy can help tumours relapse, so removing them (senolytics) is a new strategy.
Which nodes have drugs → - Chromosomal instability & aneuploidyNode: TP53 loss permits · 2 druggable nodes
Most cancers have the wrong number of chromosomes and keep shuffling them at every division. This chaos fuels evolution and drug resistance, but it also stresses the cell and can trigger immune alarms, a double edge that researchers are trying to exploit.
Which nodes have drugs → - Clonal evolution & minimal residual diseaseNode: Truncal driver clone · 1 druggable nodes
A tumour is a population that evolves by natural selection. Treatment kills the sensitive cells and selects the rest, which is why resistance is the rule; measuring the surviving population (MRD) and adapting therapy is the counter-strategy.
Which nodes have drugs → - Clonal haematopoiesis (CHIP)Node: DNMT3A, TET2, ASXL1, PPM1D, TP53 · 1 druggable nodes
As we age, blood stem cells with cancer-like mutations quietly expand in most people. These clones raise leukaemia and heart disease risk, are accelerated by chemotherapy, and confuse blood tests for cancer DNA.
Which nodes have drugs → - DNA replication stressNode: TP53 (lost) · 4 druggable nodes
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.
Which nodes have drugs → - Drivers, passengers & the two-hit modelNode: Tumour suppressor · 2 druggable nodes
Of the thousands of mutations in a tumour, only a handful (typically 2-8) actually drive it. Drivers either jam an accelerator on (oncogenes, one hit is enough) or remove a brake (tumour suppressors, both copies must go). Everything else is a passenger along for the ride.
Which nodes have drugs → - Field cancerisationNode: Mutant clones in normal tissue (NOTCH1, TP53) · 1 druggable nodes
Cancer often arises from a whole region of tissue that already carries mutations, not from one rogue cell. Sun-exposed skin, smokers' airways, and Barrett's oesophagus are patchworks of mutant clones competing long before a tumour appears.
Which nodes have drugs → - Lineage plasticity & neuroendocrine transformationNode: TP53 + RB1 loss · 5 druggable nodes
Under pressure from a drug that blocks its identity (the androgen receptor in prostate cancer, EGFR in lung cancer), a tumour can change what kind of cell it is, becoming a small-cell neuroendocrine cancer that no longer needs the blocked signal. It is the ultimate escape: not a new mutation in the engine, but a new engine.
Which nodes have drugs → - Mitosis & the spindle assembly checkpointNode: p53 arrest · 3 druggable nodes
When a cell divides, a scaffold of microtubules (the spindle) pulls one copy of each chromosome to each side. A checkpoint holds the split until every chromosome is hooked on. Taxanes and vinca alkaloids freeze the spindle so the cell is stuck at this checkpoint until it dies.
Which nodes have drugs → - Oncogenic virusesNode: p53 degraded · 3 druggable nodes
About one cancer in eight worldwide is caused by a virus. HPV, hepatitis B and C, Epstein-Barr, HTLV-1, KSHV and Merkel cell polyomavirus each hijack the same brakes cancer normally has to mutate, which is why vaccines against HPV and HBV are among the most effective anti-cancer drugs ever made.
Which nodes have drugs → - p53 / RB / cell-cycle checkpointNode: p53 · 4 druggable nodes
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.
Which nodes have drugs → - Synthetic lethality: paired dependenciesNode: TP53 loss, CCNE1 amp · 7 druggable nodes
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.
Which nodes have drugs → - The cell-cycle engine (cyclins & CDKs)Node: p21 / p27 · 4 druggable nodes
Cell division runs on a clock made of cyclins and their kinases (CDKs), each pair firing in order: D-CDK4/6 to leave rest, E-CDK2 to start copying DNA, A-CDK2 to finish, B-CDK1 to divide. Cancers speed the clock; CDK inhibitors slow it.
Which nodes have drugs → - The p53 network (guardian of the genome)Node: p53 · 4 druggable nodes
p53 is the cell's emergency coordinator. Damage, oncogene stress, or lack of oxygen switch it on; it then pauses division, orders repairs, or triggers suicide or permanent retirement. MDM2 keeps it switched off in healthy cells. Half of all cancers break p53 outright; many of the rest over-produce MDM2.
Which nodes have drugs →
Companion diagnostics and assays
Assay registry →No companion diagnostic in the registry measures this target.
Preclinical models
All models →| Cell line | Identifiers | Why it is used |
|---|---|---|
| HCT 116 | CVCL_0291 · ACH-000971 | Wild-type parent with isogenic TP53-/- derivative (Vogelstein laboratory). |
| NCI-H1299 | CVCL_0060 · ACH-000510 | TP53-null lung line used to re-express mutant alleles. |
| Saos-2 | CVCL_0548 · ACH-000410 | TP53-null osteosarcoma; classic reconstitution host. |
| MDA-MB-468 | CVCL_0419 · ACH-000849 | R273H. |
| SK-BR-3 | CVCL_0033 · ACH-000017 | R175H. |
| Huh-7 | CVCL_0336 · ACH-000480 | Y220C; the reactivator line. |
| BxPC-3 | CVCL_0186 · ACH-000535 | Y220C. |
| NUGC-3 | CVCL_1612 · ACH-000911 | Y220C gastric line. |
| MCF-7 | CVCL_0031 · ACH-000019 | Wild-type TP53; MDM2-inhibitor sensitive control. |
| SJSA-1 | CVCL_1697 · ACH-000748 | MDM2-amplified osteosarcoma; the MDM2-inhibitor standard. |
- Trp53 R172H and R270H knock-ins (Murine equivalents of human R175H and R273H) Olive et al., Cell 2004
Open questions
All open questions →- 01
Can mutant p53 be drugged directly, whether by reactivation (Y220C binders), degradation, or synthetic lethality with WEE1 or ATR?
basicresearchWhy unresolved. TP53 is the most mutated cancer gene and still has no approved drug; eprenetapopt failed, Y220C reactivators are in trials, and WEE1 and ATR inhibitors have shown activity mainly in small studies.
What would answer it. A randomised trial with a TP53-allele-selected population meeting its primary endpoint, or a mechanistic demonstration of mutant-p53 degradation with clinical response.
Source: Vogelstein et al., Science 2013
Ideas and companies
Key papers and the live literature
Preprints →- Martincorena: normal sun-exposed skin is a patchwork of cancer-mutation clones · Science 2015
- Cancer genome landscapes: about 140 driver genes, and each tumour needs only a handful · Science 2013
Query 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.
Export
The dossier as machine-readable JSON: identifiers from HGNC, Ensembl, UniProt and ChEMBL, products with status, trials, pathways, hotspots, open questions and assays. The full entity record is in the open API at /api/v1/entities/tp53.json. Licence CC BY 4.0.