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

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 suppression of an oncogenic isoform of TP73. Combined treatment with both sotorasib and SR-4835 yielded an additive response and suppressed the development of acquired resistance to either inhibitor. The inhibitor combination caused additive G1 and G2/M arrest, and the increased sensitivity of emerging drug-resistant cell populations to SR-4835 extended the duration of response over single-agent treatment in cell culture and mouse models. These results support combining KRAS and CDK12/13 inhibitors to extend the duration of response in KRAS-mutant lung cancer. Patients with acquired resistance to sotorasib may benefit from follow-up monotherapy with CDK12/13 inhibitors, the first of which, recently entered clinical trials. Targeting CDK12/13 thus offers a promising strategy to overcome or prevent resistance to KRAS inhibitors. SIGNIFICANCE: CDK12/13 is an effective target to prevent the development of acquired resistance to KRASG12C inhibitors and to treat cancers that have developed resistance, providing a combinatorial approach for optimizing KRAS-mutant tumor treatment. See related article by Solanki et al., p. 467.