Abstract 1870: Characterizing drug-induced transcriptional reprogramming in KRAS mutant lung cancer.

Abstract KRAS mutations define the largest genomic subset of non-small cell lung cancer (NSCLC). Recently, inhibitors that selectively target the KRASG12C 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 KRASG12C-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. Citation Format: Wafa Malik, Anurag Singh, Laurent Sansregret, Aaron N. Hata. Characterizing drug-induced transcriptional reprogramming in KRAS mutant lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1870.