表征KRAS突变型肺癌中药物诱导的转录重编程

KRAS mutations define the largest genomic subset of non-small cell lung cancer (NSCLC). Recently, inhibitors that selectively target the KRAS G12C mutation (G12Ci) have been developed, however, clinical responses are incomplete and short-lived due to intrinsic and adaptive drug resistance. Combination drug strategies designed to inhibit adaptive resistance by targeting reactivation of the MAPK pathway have demonstrated limited efficacy and significant dose-limiting toxicity. Therefore, new strategies to overcome drug resistance are needed. In some contexts, resistance to oncogene-directed therapies in NSCLC can be linked to dysregulation of the Hippo pathway, a key cell growth control pathway that is conserved across species. Recent preclinical studies have suggested that dysregulation of the Hippo pathway and activation of YAP and its corresponding transcription factor TEAD promote adaptive resistance in KRAS -mutant lung cancer models, which can be overcome by combining YAP-TEAD inhibitors with G12Ci. However, our mechanistic understanding of how YAP drives adaptive resistance is incomplete. Using patient-derived KRAS G12C -mutant models, we show that G12Ci induces progressive YAP-dependent and YAP-independent transcriptional reprogramming. We identify lineage programs regulated by YAP during adaptation to G12Ci that are derepressed upon co-treatment with a YAP-TEAD inhibitor. These results reveal insights into non-genomic adaptive drug resistance in lung cancer and will enable future development of rational drug combination strategies to overcome therapeutic resistance.