Crizotinib Nanomicelles Synergize with Chemotherapy through Inducing Proteasomal Degradation of Mutp53 Proteins

Abstract

TP53 missense mutations that express highly stabilized mutant p53 protein (mutp53) driving tumorigenesis have been witnessed in a considerable percentage of human cancers. The attempt to induce degradation of mutp53 has thus been an attractive strategy to realize precise antitumor therapy, but currently, there has been no FDA-approved medication for mutp53 cancer. Herein, we discovered a small molecule compound crizotinib, an FDA-approved antitumor drug, exhibited outstanding mutp53-degrading capability. Crizotinib induced ubiquitination-mediated proteasomal degradation of wide-spectrum mutp53 but not the wild-type p53 protein. Degradation of mutp53 by crizotinib eliminated mutp53-conferred gain-of-function (GOF), leading to reduced cell proliferation, migration, demise, and cell cycle arrest, as well as enhanced sensitivity to doxorubicin-elicited killing in mutp53 cancer. To alleviate the side effects and improve the therapeutic effect, we adopted poly(ethylene glycol)-polylactide-co-glycolide (PEG-PLGA) nanomicelles to deliver the hydrophobic drugs doxorubicin and crizotinib, demonstrating that crizotinib nanomicelles effectively enhanced doxorubicin-elicited anticancer efficacy in a p53Y220C pancreatic cancer in vitro and in vivo via mutp53 degradation induced by crizotinib, manifesting its promising application in clinical practice. Our work therefore revealed that crizotinib exerted significant synergistic chemotherapy with doxorubicin and suggested a novel combination therapeutic strategy for targeting p53 cancer in further clinical application.