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Ref Type Journal Article
PMID (41504628)
Authors Fece de la Cruz F, Varkaris A, Patel PS, Kushner EW, Morales-Giron AA, Lee SS, Singh A, Kim CT, Norden BL, Ehnstrom S, Riedl JM, Curtis JM, Barnes H, Kehlmann AM, Chevalier NJ, Okuma HS, Patel M, Wirth LJ, Connell B, Nugent F, Pappas L, Lau K, Juric D, Hopkins JL, Guiley KZ, Shokat KM, Gulhan DC, Parikh AR, Corcoran RB
Title Acquired On-Target Alterations Drive Clinical Resistance to p53-Y220C Reactivators.
Journal Vol Issue Date Pages Journal Short Title
Cancer discovery 16 4 2026 Apr 01 677-685 Cancer Discov
URL
Abstract Text The tumor-suppressor TP53 is the most frequently altered gene in cancer, and the Y220C hotspot, found in 1.8% of TP53-mutant tumors, creates a druggable cavity that destabilizes p53. Rezatapopt, a first-in-class, orally bioavailable reactivator of Y220C-mutant p53, has demonstrated promising initial efficacy in the phase 1/2 PYNNACLE trial. We report the first clinical mechanisms of resistance to this therapeutic class. Profiling of circulating tumor DNA, tumor biopsies, and rapid autopsy specimens upon rezatapopt progression revealed multiple heterogenous secondary TP53 alterations in cis with Y220C, including (i) DNA-binding domain mutations or frameshift/nonsense mutations that abolish transcriptional activity and (ii) mutations within the Y220C-binding surface predicted to hinder drug binding. Functional modeling confirmed that these double mutants eliminate p53 reactivation and target gene induction by rezatapopt. These findings establish a molecular framework for resistance to p53 Y220C reactivators and inform strategies to overcome resistance with next-generation agents.This study illustrates how pan-cancer resistance to Y220C-mutant p53 reactivators emerges in patients, indicating that on-target acquired alterations can represent a major mechanism of clinical resistance. These insights establish a molecular basis for therapeutic failure and provide a framework for developing next-generation agents to overcome resistance. See related commentary by Liu and Gu, p. 620.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
TP53 F109S missense loss of function TP53 F109S lies within the DNA-binding domain of the Tp53 protein (PMID: 22713868). F109S results in decreased chromatin binding and decreased binding to the promoter regions of MDM2 and CDKN1A, and decreased expression of PUMA, CDKN1A, and MDM2 genes in culture (PMID: 41504628).
TP53 L145P missense loss of function TP53 L145P lies within the DNA-binding domain of the Tp53 protein (PMID: 22713868). L145P results in decreased chromatin binding and decreased binding to the promoter regions of MDM2 and CDKN1A, and decreased expression of PUMA, CDKN1A, and MDM2 genes in culture (PMID: 41504628).
TP53 L265_G266del deletion unknown TP53 L265_G266del results in the deletion of two amino acids in the DNA-binding domain of the Tp53 protein from amino acids 265 to 266 (UniProt.org). L265_G266del has been identified in the scientific literature (PMID: 41504628), but has not been biochemically characterized and therefore, its effect on Tp53 protein function is unknown (PubMed, Apr 2026).
TP53 P151A missense loss of function - predicted TP53 P151A lies within the DNA-binding domain of the Tp53 protein (PMID: 22713868). P151A results in decreased expression of PUMA, CDKN1A, and MDM2 in culture (PMID: 41504628), and therefore, is predicted to lead to a loss of Tp53 protein function.
TP53 P151R missense loss of function TP53 P151R lies within the DNA-binding domain of the Tp53 protein (PMID: 22713868). P151R results in decreased chromatin binding and decreased binding to the promoter regions of MDM2 and CDKN1A, and decreased expression of PUMA, CDKN1A, and MDM2 genes in culture (PMID: 41504628).
TP53 P152R missense loss of function TP53 P152R lies within the DNA-binding domain of the Tp53 protein (PMID: 22713868). P152R results in decreased chromatin binding and decreased binding to the promoter regions of MDM2 and CDKN1A, and decreased expression of PUMA, CDKN1A, and MDM2 genes in culture (PMID: 41504628).
TP53 V147L missense no effect - predicted TP53 V147L lies within the DNA-binding domain of the Tp53 protein (PMID: 21760703). V147L retains the ability to bind chromatin and the promoter regions of MDM2 and CDKN1A, and to upregulate the expression of PUMA, CDKN1A, and MDM2 genes to similar levels of wild-type protein in culture (PMID: 41504628), and therefore, is predicted to have no effect on Tp53 protein function.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
TP53 Y220C head and neck carcinoma predicted - sensitive Rezatapopt Case Reports/Case Series Actionable In a Phase I/II trial (PYNNACL), Rezatapopt (PC14586) treatment resulted in a confirmed radiographic partial response lasting 5 months in a patient with metastatic HPV-negative head and neck carcinoma harboring TP53 Y220C (PMID: 41504628; NCT04585750). 41504628
TP53 F109S TP53 Y220C Advanced Solid Tumor resistant Rezatapopt Preclinical - Cell culture Actionable In a preclinical study, cancer cell lines expressing TP53 Y220C and F109S were resistant to Rezatapopt (PC14586) treatment in culture (PMID: 41504628). 41504628
TP53 P152R TP53 Y220C Advanced Solid Tumor resistant Rezatapopt Preclinical - Cell culture Actionable In a preclinical study, cancer cell lines expressing TP53 Y220C and P152R were resistant to Rezatapopt (PC14586) treatment in culture (PMID: 41504628). 41504628
TP53 L145P TP53 Y220C Advanced Solid Tumor resistant Rezatapopt Preclinical - Cell culture Actionable In a preclinical study, cancer cell lines expressing TP53 Y220C and L145P were resistant to Rezatapopt (PC14586) treatment in culture (PMID: 41504628). 41504628
TP53 P151R TP53 Y220C Advanced Solid Tumor resistant Rezatapopt Preclinical - Cell culture Actionable In a preclinical study, cancer cell lines expressing TP53 Y220C and P151R were resistant to Rezatapopt (PC14586) treatment in culture (PMID: 41504628). 41504628
TP53 Y220C TP53 N288fs Advanced Solid Tumor resistant Rezatapopt Preclinical - Cell culture Actionable In a preclinical study, cancer cell lines expressing TP53 Y220C and N288fs were resistant to Rezatapopt (PC14586) treatment in culture (PMID: 41504628). 41504628
TP53 P151A TP53 Y220C Advanced Solid Tumor resistant Rezatapopt Preclinical - Cell culture Actionable In a preclinical study, cancer cell lines expressing TP53 Y220C and P151A were resistant to Rezatapopt (PC14586) treatment in culture (PMID: 41504628). 41504628
TP53 Y220C ureter squamous cell carcinoma predicted - sensitive Rezatapopt Case Reports/Case Series Actionable In a Phase I/II trial (PYNNACL), Rezatapopt (PC14586) treatment resulted in rapid clinical symptom improvement and radiographic stable disease lasting 6 months in a patient with metastatic squamous cell carcinoma of the ureter harboring TP53 Y220C (PMID: 41504628; NCT04585750). 41504628
TP53 Y220C TP53 L265_G266del Advanced Solid Tumor resistant Rezatapopt Preclinical - Cell culture Actionable In a preclinical study, cancer cell lines expressing TP53 Y220C and L265_G266del were resistant to Rezatapopt (PC14586) treatment in culture (PMID: 41504628). 41504628
TP53 V147L TP53 Y220C Advanced Solid Tumor resistant Rezatapopt Preclinical - Cell culture Actionable In a preclinical study, cancer cell lines expressing TP53 Y220C and V147L were resistant to Rezatapopt (PC14586) treatment in culture (PMID: 41504628). 41504628
TP53 Y220C TP53 R273C Advanced Solid Tumor resistant Rezatapopt Preclinical - Cell culture Actionable In a preclinical study, cancer cell lines expressing TP53 Y220C and R273C were resistant to Rezatapopt (PC14586) treatment in culture (PMID: 41504628). 41504628
TP53 R175H TP53 Y220C Advanced Solid Tumor resistant Rezatapopt Preclinical - Cell culture Actionable In a preclinical study, cancer cell lines expressing TP53 Y220C and R175H were resistant to Rezatapopt (PC14586) treatment in culture (PMID: 41504628). 41504628
TP53 Y220C TP53 R282W Advanced Solid Tumor resistant Rezatapopt Preclinical - Cell culture Actionable In a preclinical study, cancer cell lines expressing TP53 Y220C and R282W were resistant to Rezatapopt (PC14586) treatment in culture (PMID: 41504628). 41504628
TP53 P152L TP53 Y220C Advanced Solid Tumor resistant Rezatapopt Preclinical - Cell culture Actionable In a preclinical study, cancer cell lines expressing TP53 Y220C and P152L were resistant to Rezatapopt (PC14586) treatment in culture (PMID: 41504628). 41504628
TP53 Y220C TP53 R248W Advanced Solid Tumor resistant Rezatapopt Preclinical - Cell culture Actionable In a preclinical study, cancer cell lines expressing TP53 Y220C and R248W were resistant to Rezatapopt (PC14586) treatment in culture (PMID: 41504628). 41504628