Abstract A064: Establishing the cellular and molecular impacts of the dual BRM/BRG1 inhibitor FHD-286 on pre-clinical models of non-small cell lung cancer (NSCLC)

Abstract

Abstract The BRG/BRM-associated factor (BAF) complex plays critical roles in chromatin regulation. Within this complex, the two mutually exclusive ATPases BRM and BRG1 (SMARCA2 and SMARCA4, respectively) drive chromatin remodeling activity. Genetic alterations in the SMARCA4 gene, encoding BRG1, are found in approximately 10% of non-small cell lung cancer (NSCLC) patients, leaving this subset of BRG1-deficient tumors highly susceptible to BRM inhibition. In addition, BRG1 has oncogenic activity in NSCLC, rationalizing the use of a dual BRM/BRG1 ATPase inhibitor, such as the highly potent clinical stage compound FHD-286, in NSCLC patients, regardless of SMARCA4 status. Here, we demonstrate that a panel of NSCLC cell lines respond to dual BAF ATPase inhibition in both in vitro and in vivo settings, regardless of SMARCA4 mutation status. Interestingly, dual BRM/BRG1 inhibition in cell lines reduces chromatin accessibility at motifs normally bound by AP-1 transcription factors, which play tumorigenic roles in NSCLC. We also find that expression of the stemness-associated glycoprotein CD44 is decreased by FHD-286, suggesting that dual BRM/BRG1 inhibition impacts the differentiation state of NSCLC. Moreover, transcriptional analyses of NSCLC xenograft models reveal that a basal cell gene expression signature, which is associated with a less differentiated cell state, is downregulated by FHD-286 treatment. Finally, genome-wide CRISPR knockout screening with FHD-286 in 2 NSCLC lines further elucidates mechanisms of action and molecular vulnerabilities induced by dual BAF ATPase inhibition. Collectively, these results indicate a path forward for the development of FHD-286 for the treatment of NSCLC patients. Citation Format: Molly M. Wilson, Ammar Adam, Victoria Amaral, Oliver Mikse, GiNell Elliott, David L. Lahr, Ashley K. Gartin, Jessica Wan, Liv Johannessen, Kana Ichikawa, Katharine Feldman, Jessica Piel, Gabriel J. Sandoval, Richard C. Centore, Steven F. Bellon, Martin Hentemann. Establishing the cellular and molecular impacts of the dual BRM/BRG1 inhibitor FHD-286 on pre-clinical models of non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A064.