A novel MDM2-p53 antagonist APG115 exerts synergistic effect with ibrutinib via targeting MCL-1 in chronic lymphocytic leukemia

Abstract APG115 is a highly selective small-molecule inhibitor of MDM2-p53 interaction with oral activity, which restores p53 activation in patients with solid tumors in clinical trials. The Bruton tyrosine kinase inhibitor (BTKi) ibrutinib exhibits significant efficacy in chronic lymphocytic leukemia (CLL) patients including high-risk patients. However, the chemoresistance of ibrutinib still needs to be addressed urgently. Herein, we first demonstrated that the APG115 exerted apoptogenic and antiproliferative effects, and induced G0/G1 cell cycle arrest in CLL. As an agent used either alone or in combination with ibrutinib together, APG115 provided remarkable antitumor activity and overall survival extension in vivo. Mechanistically, the activation of p53 positively regulates the p53/p21 pathway, prompting MCL-1 degradation via inducing its ubiquitination. On basis of the upregulation of MCL-1 in CLL cells with ibrutinib resistance, these evidences explain how APG115 reduces the resistance of ibrutinib in CLL. This study offers promising prospects to constitute effective regimens of APG115 combined with ibrutinib for the CLL treatment.