Targeting CDK12/13 Drives Mitotic Arrest to Overcome Resistance to KRASG12C Inhibitors.

ABSTRACT: The onset of acquired resistance limits the efficacy of KRASG12C inhibitors in patients with lung cancer. Experiments in preclinical model systems and retrospective analyses of patients treated with these inhibitors have both suggested that the activation of DNA repair pathways and G2/M kinases is common in lung cancers with acquired resistance to KRASG12C inhibitors. In this study, we identified a shared vulnerability to the CDK12/13-selective inhibitor SR-4835 in several KRASG12C-mutant cell lines with acquired resistance to sotorasib. In pairs of KRASG12C-mutant parental and sotorasib-resistant cell lines, CDK12/13 inhibition suppressed DNA repair gene expression and induced mitotic arrest, which was exacerbated in sotorasib-resistant cells by failure to activate the G2/M checkpoint and

SUBMITTER: Stern YE 

PROVIDER: S-EPMC12638015 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature