Abstract LB451: Targeting oncogenic transcription and signaling crosstalk fueling drug resistance in lung cancer

Abstract Lung cancer is the leading cause of all cancer-related mortality worldwide. The RAS-RAF-MEK-ERK (RAS-MAPK) signaling pathway is critical for maintaining cell survival and proliferation. Somatic mutations in the RAS or RAF genes are associated with frequent hyper-activation of RAS-MAPK pathway in non-small cell lung cancer or NSCLC. While direct inhibitors of KRAS G12C are emerging with promising efficacy, resistance to these agents as well as to inhibitors of RAF and MEK remains an obstacle to long-term patient survival. Therefore, it is essential to understand how drug resistance emerges in lung cancer and to identify bypass survival pathways or compensatory mechanisms that limit the response to RAS-MAPK targeted therapies in lung cancer. Emerging literature indicates a critical role of bromodomain and extra-terminal domain (BET) family of bromodomain proteins (BRD4, BRD3, BRD2) in various human malignancies and provides the rational for targeting BET proteins as a strategy for the development of new anticancer drugs. Using combinatorial drug screens in a panel of NSCLC cell lines, we found that BET proteins act in parallel to the RAS-MAPK pathway to promote drug resistance in lung cancer. 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 synergistic apoptosis induction and downregulation of MYC, a transcriptional target of BET proteins. However, concurrent loss of the tumor suppressor STK11 (aka LKB1) in NSCLC cells induced activation of the Hippo pathway effector and transcriptional co-activator, YAP and conferred resistance to the BET and RAS-MAPK inhibitors combination in NSCLC cells and tumors. These findings suggest an unprecedented functional interplay between BET chromatin regulators, Hippo-YAP and RAS-MAPK signaling in lung cancer and therapy resistance. Further, this study identified STK11 as a modifier of sensitivity to the BET and RAS-MAPK inhibitors combination in NSCLC cells and tumors. Citation Format: Nilanjana Chatterjee, Victor Olivas, Wei Wu, Tracy Tang, Ben Powell, Trever Bivona. Targeting oncogenic transcription and signaling crosstalk fueling drug resistance in lung cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr LB451.