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

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.