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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 4 products (1 approved), 18 trials, 26 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.
Transcription factor coordinating cell-cycle arrest, apoptosis, and senescence after DNA damage.
| 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 |
| Small-cell lung cancer | 86-100% | Biallelic inactivation | cBioPortal: 103 of 120, 85.8%, carry a non-synonymous TP53 mutation in sclc_ucologne_2015. Whole-genome sequencing of 110 small-cell lung cancers found biallelic inactivation of TP53 in nearly all tumours, sometimes through complex genomic rearrangement rather than point mutation, which is why a mutation call alone reads lower (George 2015). | cBioPortal (TCGA) |
| Non-small-cell lung cancer | 83-94% | Mutation | cBioPortal: 404 of 484, 83.5%, in lusc_tcga_pan_can_atlas_2018; 149 of 178, 83.7%, in lusc_tcga_pub; 102 of 108, 94.4%, in lusc_cptac_2021. The founding paper reported mutation of TP53 in nearly all specimens, alongside a mean of 360 exonic mutations, 165 genomic rearrangements and 323 segments of copy-number change per tumour (Cancer Genome Atlas Research Network 2012). | cBioPortal (TCGA) |
| Triple-negative breast cancer | 80-85% | TP53 mutation (basal-like) | cBioPortal (TCGA) | |
| Triple-negative breast cancer | 80% | Mutation | 80% of basal-like tumours in the TCGA breast study (Cancer Genome Atlas 2012); 81% of 447 sequenced TNBCs from METABRIC and TCGA, 92% in the BL1 subtype (Bareche 2018); cBioPortal: 67 of 84 exome-sequenced triple-negative samples, 79.8%, in brca_tcga_pub and 100 of 123, 81.3%, on the 2018 calls; 237 of 299, 79.3%, in brca_metabric; 159 of 176 samples, 90.3%, in breast_msk_2018. TP53, PIK3CA and PTEN mutations were the clonally dominant events in 104 primary TNBCs (Shah 2012). | doi.org |
| Pancreatic ductal adenocarcinoma | 70-75% | TP53 mutation | cBioPortal (TCGA) | |
| Pancreatic ductal adenocarcinoma | 66-76% | Mutation | cBioPortal: 1,778 of 2,336, 76.1%, in pdac_msk_2024; 286 of 395, 72.4%, in pancreas_msk_2024; 105 of 140, 75.0%, in paad_cptac_2021; 253 of 383, 66.1%, in paad_qcmg_uq_2016; 55 of 109, 50.5%, in paad_utsw_2015; 107 of 179, 59.8%, in paad_tcga_pan_can_atlas_2018; 33 of 99 in paad_icgc on 2012 exome depth. Hotspots R175H, R248Q, R248W, R273H and R273C recur. 44.5% of KRAS wild-type tumours (Philip 2022); the squamous subtype is enriched for TP53 and KDM6A mutation (Bailey 2016). | cBioPortal (TCGA) |
| Gallbladder cancer | 63% | Mutation | 63% of 244 MSK-IMPACT samples (Giraldo 2022; cBioPortal gbc_mskcc_2022 counts 154 of 244 sequenced samples, 63.1%); 59% of 85 gallbladder carcinomas on FoundationOne (Javle 2016); 54% of 376 Indian patients (Suryavanshi 2025); 47.1% of 57 Chinese tumour-normal pairs (Li 2014); 30% of 56 Chilean tumours on the Oncomine Comprehensive Assay (Erices 2025); the most mutated gene in 190 patients (Nepal 2021). | doi.org |
| Colorectal cancer | 52-73% | Mutation (with 17p loss) | cBioPortal: 5,295 of 7,237, 73.2%, in crc_msk_2026; 824 of 1,134, 72.7%, in crc_msk_2017; 1,107 of 1,516, 73.0%, in crc_eo_2020; 314 of 534, 58.8%, in coadread_tcga_pan_can_atlas_2018; 121 of 224, 54.0%, in coadread_tcga_pub; 320 of 619, 51.7%, in coadread_dfci_2016. Loss of chromosome 17p sequences was found in 75% of carcinomas but only rarely in early adenomas in the 172 specimens that built the genetic model (Vogelstein 1988). | cBioPortal (TCGA) |
| Colorectal cancer | 55-60% | TP53 mutation | cBioPortal (TCGA) | |
| Non-small-cell lung cancer | 46-54% | Mutation | cBioPortal: 1,429 of 2,653, 53.9%, in luad_mskcc_2023_met_organotropism; 485 of 915, 53.0%, in lung_msk_2017; 295 of 566, 52.1%, in luad_tcga_pan_can_atlas_2018; 107 of 230, 46.5%, in luad_tcga_pub; 59 of 110, 53.6%, in luad_cptac_2020; 109 of 302, 36.1%, in luad_oncosg_2020; 36 of 232, 15.5%, in lung_nci_2022. | cBioPortal (TCGA) |
| Prostate cancer | 3-41% | Inactivating mutation, with deep deletion on top | cBioPortal mutation: 16 of 477, 3.4%, in prad_cpcg_2017 and 26 of 313, 8.3%, in prostate_dkfz_2018, both localised whole-genome cohorts; 57 of 494, 11.5%, in prad_tcga_pan_can_atlas_2018; 189 of 1,013, 18.7%, in prad_p1000; 129 of 424, 30.4%, in prad_mcspc_mskcc_2020; 650 of 2,260, 28.8%, in prostate_msk_2024; 163 of 444, 36.7%, in prad_su2c_2019; 58 of 150, 38.7%, in prad_su2c_2015; 57 of 141, 40.4%, in prad_fhcrc; 25 of 61, 41.0%, in prad_mich. Deep deletion adds 2 to 15% depending on cohort. | 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.
| 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.
| Modality | Approved | Phase 3 | Phase 2 | Withdrawn or failed |
|---|---|---|---|---|
| Small molecule 3 | - | |||
| Vaccine or virus 1 | - | - | - |
| Trial | 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. | - |
| 3 | Active | A Phase 3, Multicenter, Randomized, Open Label Study of Etentamig Compared With Standard Available Therapies in Subjects With Relapsed or Refractory Multiple Myeloma (3L+ RRMM Monotherapy Study) | - | ||
| 3 | Active | A Phase 1/3 Study to Evaluate Efficacy and Safety of Selinexor, a Selective Inhibitor of Nuclear Export, in Combination With Ruxolitinib in Treatment-naïve Patients With Myelofibrosis | - | ||
| 3 | Recruiting | A Randomised, Open-label, Phase 3 Trial Comparing the Efficacy and Safety of OSE2101 Versus Docetaxel in HLA-A2 Positive Patients With Metastatic Non-Small Cell Lung Cancer (NSCLC) With Secondary Resistance to Immune Checkpoint Inhibitor | - | ||
| 2/3 | Active | A Phase 2/3, Multicenter Randomized Study of Rituximab-Gemcitabine-Dexamethasone-Platinum (R-GDP) With or Without Selinexor in Patients With Relapsed/Refractory Diffuse Large B-cell Lymphoma (RR DLBCL) | - | ||
| 2/3 | Recruiting | A Phase 2/3 Study of Navtemadlin as Maintenance Therapy in Subjects With TP53WT Advanced or Recurrent Endometrial Cancer Who Responded to Chemotherapy | - | ||
| 2 | Recruiting | A Phase 2b, Open-label, Multi-arm Clinical Trial of Selinexor Plus Low-dose Dexamethasone (Sd) in Patients With Penta-refractory Multiple Myeloma or Selinexor and Bortezomib Plus Low-dose Dexamethasone (SVd) in Patients With Triple-class Refractory Multiple Myeloma | - | ||
| 2 | Active | A Two-Part, Randomized, Open-label, Multicenter, Phase 2a/2b Study of the Efficacy, Safety, and Pharmacokinetics of KRT-232 Compared to Ruxolitinib in Patients With Phlebotomy-Dependent Polycythemia Vera | - | ||
| 2 | Completed | PiSARRO-R: p53 Suppressor Activation in Platinum-Resistant High Grade Serous Ovarian Cancer, a Phase II Study of Systemic Pegylated Liposomal Doxorubicin Chemotherapy With APR-246 | - | ||
| 2 | Active | A Phase 2b Open-label Study of Selinexor (KPT-330) in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL) | - | ||
| 2 | Active | A Phase II Trial of Daratumumab, Lenalidomide and Dexamethasone (DRd) in Combination With Selinexor for Patients With Newly Diagnosed Multiple Myeloma | - | ||
Using Tumor Models to Determine Treatments NCT06813079 | 2 | Recruiting | ADOPT: Adaptive Organoid-Based Precision Therapy Study in Pancreatic Cancer - A Prospective Single-Arm Phase II Trial | - | |
| 1/2 | Recruiting | A Phase 1/2a Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of NTS071 in Subjects With Advanced Solid Tumors Harboring a TP53 Y220C Mutation | - | - | |
| 1/2 | Recruiting | A Multicenter, Phase 1/2, Dose-finding and Dose Expansion Study of OSE-279, a PD-1 Blocking Monoclonal Antibody, in Subjects With Advanced Solid Tumors or Lymphomas | - | ||
| 1/2 | Recruiting | An Open-Label, Multicenter, Phase 1b/2 Study of the Safety and Efficacy of KRT-232 in Combination With Acalabrutinib in Subjects With Relapsed/Refractory Diffuse Large B-cell Lymphoma or Relapsed/Refractory Chronic Lymphocytic Leukemia | - | ||
| 1/2 | Recruiting | Phase I Dose Finding Study of Selinexor and Talazoparib in Patients With Advanced Refractory Solid Tumors, Followed by Phase II Expansion Cohort Study in Patients With Advanced/ Metastatic Triple Negative Breast Cancers. (START) | - | ||
| 1/2 | Recruiting | A Phase 1b/2 Study of Selinexor (KPT-330) in Combination With Backbone Treatments for Relapsed/Refractory Multiple Myeloma and Newly Diagnosed Multiple Myeloma | - |
Conversion to small-cell lung cancer (RB1/TP53 co-loss) or squamous histology; EGFR mutation persists but the cell no longer depends on it.
RB1/TP53 loss enables transdifferentiation; AR-indifferent, DLL3-positive, PSMA-negative.
KEGG's basal cell carcinoma map is the Hedgehog pathway: loss of the brake PTCH1 or activation of SMO leaves GLI transcription factors permanently on. Hedgehog inhibitors (vismodegib, sonidegib) shut this down in advanced disease.
Which nodes have drugs →KEGG's breast cancer map lays out the three clinical subtypes as signalling routes: oestrogen receptor driving cyclin D and CDK4/6 in hormone-receptor-positive disease, HER2 driving PI3K/AKT and MAPK in HER2-positive disease, and EGFR, Notch, Wnt and BRCA defects in triple-negative disease. Each route has its own drug class.
Which nodes have drugs →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 →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 →KEGG's CML map is built around one fusion protein, BCR-ABL1, a kinase that never switches off and drives RAS, PI3K and STAT5 signalling. Because a single enzyme causes the disease, a single class of pill (imatinib and its successors) controls it in most patients.
Which nodes have drugs →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 →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 →This KEGG map traces the step-by-step genetic route from normal bowel lining to colorectal cancer: APC loss unleashes Wnt, KRAS mutation drives growth, then TP53 and TGF-beta/SMAD4 loss remove the last brakes, or alternatively mismatch repair fails and mutations pile up. Knowing which route a tumour took decides which drugs work.
Which nodes have drugs →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 →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 →KEGG's endometrial cancer map shows oestrogen-related type I tumours with PTEN loss, KRAS and beta-catenin mutations and faulty mismatch repair, and type II tumours with TP53 mutation and HER2 amplification. Immunotherapy for mismatch-repair-deficient tumours and HER2-directed therapy follow directly from this split.
Which nodes have drugs →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 →This KEGG map splits stomach cancer into two routes: the intestinal type that accumulates TP53, APC and HER2 changes step by step, and the diffuse type driven by loss of the cell glue E-cadherin plus MET or FGFR2 amplification. It matters because HER2, FGFR2, claudin 18.2 and PD-1 status now decide first-line treatment.
Which nodes have drugs →This KEGG map shows how hepatitis viruses, alcohol and aflatoxin leave the liver with mutations in telomerase, TP53, Wnt/beta-catenin, PI3K/AKT/mTOR and the oxidative stress sensor NRF2, which together drive liver cancer. It matters because the map explains why liver cancer is treated mainly with angiogenesis blockers and immunotherapy rather than a single targeted drug.
Which nodes have drugs →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 →This KEGG map collects the small RNA molecules (microRNAs) that are switched up or down in nine common cancers and shows which oncogenes and tumour suppressors they silence. It matters because a single microRNA can dial down dozens of genes at once, so losing or gaining one reshapes whole signalling routes.
Which nodes have drugs →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 →KEGG's non-small cell lung cancer map shows a set of alternative on-switches (EGFR mutation, KRAS mutation, EML4-ALK, RET and MET alterations) that all feed the same RAS/ERK, PI3K/AKT and STAT relays, plus loss of the p16 and p53 brakes. Each on-switch now has its own targeted pill, which is why molecular testing comes before treatment.
Which nodes have drugs →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 →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 →This KEGG map shows the order of genetic hits that turn normal pancreatic duct cells into ductal adenocarcinoma: KRAS mutation first, then loss of the p16 brake, then loss of TP53, SMAD4 and BRCA2. It matters because nearly every pancreatic cancer is driven by KRAS, which until recently had no drug.
Which nodes have drugs →KEGG's small cell lung cancer map shows a tumour with both master brakes removed, RB1 and TP53, plus amplified MYC pushing the cell cycle and PTEN loss and BCL2 keeping cells alive. Chemotherapy with PD-L1 antibodies and the DLL3 T-cell engager tarlatamab are the current answers.
Which nodes have drugs →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 →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 →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.
Which nodes have drugs →This KEGG map shows thyroid cancers driven by one relay, the MAPK pathway: RET or NTRK fusions and BRAF mutations in papillary tumours, RAS mutations or PAX8-PPARG fusion in follicular tumours, and TP53 loss marking anaplastic cancer. It matters because RET, NTRK and BRAF alterations each have their own drug, and MAPK blockade can restore iodine uptake.
Which nodes have drugs →No companion diagnostic in the registry measures this target.
| 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. |
Why 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.
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.
The dossier as machine-readable JSON, at /api/v1/dossiers/tp53.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-NC 4.0.