2. Academic Validation
  3. Cabozantinib selectively induces proteasomal degradation of p53 somatic mutant Y220C and impedes tumor growth

Cabozantinib selectively induces proteasomal degradation of p53 somatic mutant Y220C and impedes tumor growth

  • J Biol Chem. 2025 Feb;301(2):108167. doi: 10.1016/j.jbc.2025.108167.
Fang Lin Lv 1,  Lu Zhang 1,  Cheng Ji 2,  Lei Peng 1,  Mingxian Zhu 1,  Shumin Yang 1,  Shunli Dong 1,  Mingxuan Zhou 1,  Fanfan Guo 1,  Zhenyun Li 1,  Fang Wang 3,  Youguo Chen 3,  Jinhua Zhou 3,  Xingcong Ren 3,  Genhai Shen 1,  Jin-Ming Yang 4,  Bin Li 5,  Yi Zhang 6
Affiliations

Affiliations

  • 1 Department of Hepatopancreatobiliary Surgery, Suzhou Ninth Hospital Affiliated to Soochow University, Suzhou, Jiangsu, China; Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.
  • 2 Department of Respiratory Medicine, First Affiliated Hospital, Soochow University, Suzhou, Jiangsu, China.
  • 3 Department of Gynecology and Obstetrics, First Affiliated Hospital, Soochow University, Suzhou, Jiangsu, China.
  • 4 Department of Cancer Biology and Toxicology, Markey Cancer Center, University of Kentucky, College of Medicine, Lexington, Kentucky, USA.
  • 5 Department of Hepatopancreatobiliary Surgery, Suzhou Ninth Hospital Affiliated to Soochow University, Suzhou, Jiangsu, China; Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China. Electronic address: bli4004@suda.edu.cn.
  • 6 Department of Hepatopancreatobiliary Surgery, Suzhou Ninth Hospital Affiliated to Soochow University, Suzhou, Jiangsu, China; Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China. Electronic address: zhangyi@suda.edu.cn.
PMID: 39793887 DOI: 10.1016/j.jbc.2025.108167
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.

Keywords

USP7; cabozantinib; p53Y220C; proteasomal degradation; tumor cells.

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