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

ABSTRACT: 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. Mechanisti

SUBMITTER: Yang Q 

PROVIDER: S-EPMC12664909 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature