What research findings exist regarding the p53 enzyme?

2026-09-14

Encoded by the TP53 gene, p53 is not a classical enzyme, but rather a key tumour suppressor transcription factor monitoring genome integrity and the cell cycle ("the guardian of the genome"). Research indicates that the inactivation or mutation of TP53 is one of the most common and most unfavourable prognostic events in human tumours, particularly in acute myeloid leukaemia (AML), myelodysplastic syndrome (MDS), colorectal cancer, non-small cell lung cancer (NSCLC), and breast cancer. In clinical trials, mutation-specific reactivators (e.g., rezatapopt/PC14586 for the Y220C mutation), sequential hypomethylating agents, and combined immunotherapy approaches are being investigated to overcome the treatment resistance caused by TP53 mutations.\n\nIn terms of its biological role, p53 coordinates DNA repair, apoptosis, and cellular ageing (senescence). In myeloid neoplasms (AML, MDS), biallelic or multi-hit TP53 alterations are associated with severe genomic instability, therapeutic resistance, and markedly poor survival, where despite combinations of hypomethylating agents and venetoclax, the majority of patients relapse.\n\nIn solid tumours, such as colorectal carcinoma and lung adenocarcinoma, pathogenic TP53 mutations signal an increased metastatic propensity and resistance to conventional therapy, whereas certain substitutions (such as mutations at codon H179) induce metabolic reprogramming by increasing lipid synthesis.\n\nIn targeted therapeutic development, rezatapopt (PC14586) and other small molecules aim to stabilise the specific structural TP53 Y220C mutation, while active clinical trials are also evaluating immunotherapy combinations and synthetic lethality-based strategies.

References

  1. TP53 in myeloid neoplasms doi:10.3324/haematol.2026.s1.6
  2. TP53 mutation at codon 179 metabolically reprograms cancer cells to promote invasion pmid:22588877
  3. Studying the Impact of Tp53 Mutations on Colorectal Cancer Pathogenesis and Therapeutic Response in a Tunisian Population doi:10.21203/rs.3.rs-9381448/v1
  4. Targeting TP53 in triple-negative breast cancer: Molecular pathogenesis, therapeutic implications, and emerging pharmacological strategies. PMID 42711224
  5. Breaking the guardian of the genome: TP53 dysfunction in myeloid neoplasms. PMID 42331069
  6. A Study to Investigate the Effects of Multiple Doses of Rezatapopt on the Pharmacokinetics of Metformin, Rosuvastatin, Repaglinide, and Midazolam in Patients With Advanced Solid Tumors Harboring a TP53 Y220C Mutation. NCT07372625
  7. The Evaluation of PC14586 in Patients With Advanced Solid Tumors Harboring a TP53 Y220C Mutation (PYNNACLE) NCT04585750

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