Small-Molecule NSC59984 Induces Mutant p53 Degradation through a ROS-ERK2-MDM2 Axis in Cancer Cells.

Increased reactive oxygen species (ROS) and hyperstabilized mutant p53 are common in cancer. Hyperstabilized mutant p53 contributes to its gain of function (GOF) which confers resistance to chemotherapy and radiotherapy. Targeting mutant p53 degradation is a promising cancer therapeutic strategy. We used a small-molecule NSC59984 to explore elimination of mutant p53 in cancer cells, and identified an inducible ROS-ERK2-MDM2 axis as a vulnerability for induction of mutant p53 degradation in cancer cells. NSC59984 treatment promotes a constitutive phosphorylation of ERK2 via ROS in cancer cells. The NSC59984-sustained ERK2 activation is required for MDM2 phosphorylation at serine-166. NSC59984 enhances phosphorylated-MDM2 binding to mutant p53, which leads to mutant p53 ubiquitination and degradation. High cellular ROS increases the efficacy of NSC59984 targeting mutant p53 degradation and antitumor effects. Our data suggest that mutant p53 stabilization has a vulnerability under high ROS cellular conditions, which can be exploited by compounds to target mutant p53 protein degradation through the activation of a ROS-ERK2-MDM2 axis in cancer cells. IMPLICATIONS: An inducible ROS-ERK2-MDM2 axis exposes a vulnerability in mutant p53 stabilization and can be exploited by small-molecule compounds to induce mutant p53 degradation for cancer therapy. ©2022 The Authors; Published by the American Association for Cancer Research.