Abstract 5510: Targeting BET, Hippo-YAP and RAS-MAPK signaling interplay in lung cancer and therapy resistance

Abstract Identifying alternate survival pathways or compensatory mechanisms that limit the response to targeted therapy is critical to discover effective combinatorial strategies for lung cancer treatment and prevention of drug resistance.Using a combinatorial drug screen in a panel of non-small cell lung cancer (NSCLC) cell lines, we identified a functional interplay between RAS-MAPK pathway oncoproteins and BET chromatin regulators in non-small cell lung cancer (NSCLC). We found that combination of BET and RAS-MAPK inhibitors caused pronounced cell death and potent tumor regression/ stasis in several KRAS or BRAF mutant models of NSCLC with potent apoptosis induction, pro-apoptotic BIM upregulation, and pro-survival MYC and BIRC5 (Survivin) downregulation. However, NSCLC cells and tumors with co-occurring alterations in the tumor suppressor STK11 were found to be partially sensitive/ resistant to the BET and RAS-MAPK inhibitors combination. By modeling STK11 deficiency in NSCLC cells and tumors, we further found that STK11 loss creates an unprecedented dependence on YAP/TEAD TFs in lung cancer. STK11 silencing in NSCLC cells resulted in the nuclear translocation of the Hippo pathway effector, YAP and activation of YAP targets, conferred resistance to RAS-MAPK inhibitors and their combination with BET inhibitors and restored cell viability. Furthermore, phenocopying STK11 loss, constitutively active 5SAYAP mitigated the deleterious effects of BET and RAS-MAPK co-inhibition in STK11-proficient NSCLC cells with concomitant upregulation of YAP targets, such as, MYC and BIRC5. Conversely, YAP/TEAD suppression re-sensitized STK11-deficient NSCLC cells and tumors to BET and RAS-MAPK inhibitors combination and induced apoptosis, pronounced loss in cell viability, and tumor regression.This study uncovered a functional interplay between BET chromatin regulators, YAP/TEAD TFs and RAS-MAPK oncoproteins that drives therapy resistance in lung cancer, specifically upon loss of key tumor suppressors, such as, STK11 and suggests rational combinatorial strategies with BET, TEAD and RAS-MAPK inhibitors. Citation Format: Nilanjana Chatterjee, Victor Olivas, Wei Wu, Tracy Tang, Ben Powell, Trever Bivona. Targeting BET, Hippo-YAP and RAS-MAPK signaling interplay in lung cancer and therapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5510.