CDK12/13 inhibition in NSCLC cell lines with acquired resistance to sotorasib

The efficacy of KRAS-G12C inhibitors in lung cancer is limited by the rapid onset of acquired resistance. While divergent mechanisms of resistance across patients and preclinical models have complicated efforts to identify therapeutic strategies for sotorasib-resistant cancers, we found that sotorasib-resistant H358 and LU65 cell lines, which have distinct mechanisms of resistance and drug sensitivity profiles, both exhibited increased vulnerability to treatment with SR-4835, an inhibitor of the transcriptional kinases CDK12 and CDK13. To identify CDK12/13-dependent genes linked to the increased sensitivity we observed in sotorasib-resistant over parental cells, we treated parental and sotorasib-resistant H358 and LU65 cells with SR-4835 and performed RNA sequencing. Overall design: Whole-transcriptome RNA sequencing was performed in three independent biological replicates of parental and sotorasib-resistant H358 and LU65 cell lines after 24-hour treatment with 0.1% DMSO or 100 nM SR-4835.