Related Experiment Video

Updated: Jan 13, 2026

Yeast As a Chassis for Developing Functional Assays to Study Human P53
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Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

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Acquired On-Target Alterations Drive Clinical Resistance to p53-Y220C Reactivators

Ferran Fece de la Cruz1, Andreas Varkaris1, Parasvi S Patel1

  • 1Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts.

Cancer Discovery
|January 8, 2026
PubMed

Insights

Resistance to Y220C-mutant p53 reactivators like rezatapopt emerges through secondary TP53 mutations. These mutations hinder drug binding and abolish p53 reactivation, impacting cancer therapy effectiveness.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Development

Background:

  • The TP53 gene is frequently altered in cancer, with the Y220C mutation creating a targetable cavity.
  • Rezatapopt is a novel therapeutic agent designed to reactivate Y220C-mutant p53.

Purpose of the Study:

  • To investigate the clinical mechanisms of resistance to Y220C-mutant p53 reactivators.
  • To identify secondary genetic alterations conferring resistance to rezatapopt.

Main Methods:

  • Profiling of circulating tumor DNA, tumor biopsies, and autopsy specimens.
  • Functional modeling of TP53 double mutants.
  • Analysis of resistance mechanisms in patients treated with rezatapopt.

Main Results:

  • Identified heterogeneous secondary TP53 alterations in cis with Y220C upon rezatapopt progression.
  • These alterations include mutations in the DNA-binding domain and within the Y220C binding surface.
  • Functional studies confirmed these double mutations abolish p53 reactivation and target gene induction by rezatapopt.

Conclusions:

  • Established a molecular framework for resistance to p53 Y220C reactivators.
  • Findings inform strategies for developing next-generation agents to overcome resistance.
  • Understanding resistance mechanisms is crucial for optimizing TP53-targeted cancer therapies.

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