Article
Acquired On-Target Alterations Drive Clinical Resistance to p53-Y220C Reactivators.
Cancer discovery - 1 Apr 2026
Fece de la Cruz Ferran, Varkaris Andreas, Patel Parasvi S, Kushner Elijah W, Morales-Giron Alvin A, Lee Sangmi Sandra, Singh Ankit, Kim Clara T, Norden Bryanna L, Ehnstrom Sara, Riedl Jakob M, Curtis Jacquelyn M, Barnes Haley, Kehlmann Allison M, Chevalier Nicholas J, Okuma Hitomi S, Patel Manisha, Wirth Lori J, Connell Brendan, Nugent Francis, Pappas Leontios, Lau Kayao, Juric Dejan, Hopkins Jessica L, Guiley Keelan Z, Shokat Kevan M, Gulhan Doga C, Parikh Aparna R, Corcoran Ryan B
Abstract excerpt
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...
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