Abstract

Inactivation of p53 by mutations commonly occurs in human cancer. The mutated p53 proteins may escape proteolytic degradation and exhibit high expression in tumors and acquire gain-of-function activity that promotes tumor progression and chemo-resistance. Therefore, selectively targeting of the gain-of-function p53 mutants may serve as a promising therapeutic strategy for cancer prevention and treatment. In this study, we identified cabozantinib, a multikinase inhibitor currently used in the clinical treatment of several types of cancer, as a selective inducer of proteasomal degradation of the p53-Y220C mutant. We demonstrate that cabozantinib disrupts the interaction between p53Y220C and USP7, a deubiquitylating enzyme, resulting in the dissociation of p53Y220C protein from its binding with USP7 and subsequent ubiquitination and degradation mediated by CHIP (the carboxyl terminal of Hsp70-interacting protein). We also show that cabozantinib displays preferential cytotoxicity to p53Y220C-harboring cancer cells both in vitro and in vivo. This study demonstrates a novel, p53-Y220C mutant–targeted anticancer action and mechanism for cabozantinib and provides the rationale for use of this drug in the treatment of cancers that carry the p53-Y220C mutation.

Document Type

Article

Publication Date

2025

Notes/Citation Information

© 2025 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.jbc.2025.108167

Funding Information

This work was supported by grants from National Natural Sciences Foundation of China to Yi Zhang (81773749, 81973352, 82273944), sponsored by the Qing Lan Project (to Yi Zhang) and by a project funded by the Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD), and supported by Gusu Health Top-Notch Youth Talent of Suzhou Health Commission (No. GSWS2019086), Wujiang Health Key Talent of Wujiang Health Commission and Suzhou Science and Technology Bureau to Bin Li and Genhai Shen (No. SKY2021022 and SKY2022031), and supported by grants from Suzhou science and technology plan project (SLJ202003) and Suzhou medical and health technology innovation projects (SKY2022045) to Cheng Ji.

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