Related Experiment Video
Updated: Jan 13, 2026
14:57
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
Summary
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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