KSQ‐4279, an Inhibitor of Ubiquitin Specific Peptidase 1, Enhanced the Chemotherapeutic Efficacy in ABCB1/ABCG2/ABCC1‐Mediated Multidrug Resistant Cancers

Multidrug resistance (MDR) remarkably hinders the success of clinical chemotherapy in carcinomas. The ATP‐binding cassette (ABC) transporter as ABCB1, ABCG2, and ABCC1 are most crucial to drive MDR. Regrettably, no MDR modulators have been accepted in clinic. Herein, KSQ‐4279, a first‐in‐class ubiquitin‐specific peptidase 1 (USP1) inhibitor in clinical development, was found as a pan‐MDR modulator. Our study showed that KSQ‐4279 strikingly intensified the cytotoxicity of multiple classical chemotherapeutic drugs in ABCB1/ABCG2/ABCC1‐induced MDR cancers independent of its own cytotoxicity in vitro, and remarkably improved chemotherapeutic efficacy not only in ABCB1/ABCG2/ABCC1‐overexpressing tumor xenografts in vivo, but also in ABCB1‐overexpressing clinical lung cancers ex vivo. Mechanistically, KSQ‐4279 weakened ABCB1/ABCG2/ABCC1 efflux function, thus increasing drugs’ reservation in cells; more specifically, it was achieved by KSQ‐4279 activating the ATPase activity and competing for the substrate‐binding pockets of ABCB1/ABCG2/ABCC1. Besides, at the effective reversal concentrations, KSQ‐4279 neither altered expression and localization of ABCB1/ABCG2/ABCC1, nor affected USP1's potential downstream AKT or ERK1/2 signaling. This is the first study to investigate the combination of USP1 inhibitor (KSQ‐4279) with traditional chemotherapeutic drugs in reversing MDR, which surprisingly hinted ABCB1, ABCG2, and ABCC1 as the new targets of KSQ‐4279, and advocated this promising combination therapy in clinical refractory MDR cancers.