Abstract A079: FHD286 is a BRG1/BRM ATPase inhibitor showing efficacy in NSCLC models and is applicable to NSCLC patients both as a single agent treatment and in combination with current standards of care

Abstract

Abstract The BAF (BRG/BRM-associated factors) complex plays a critical role in shaping the chromatin landscape. The two mutually exclusive ATPases BRM/BRG1 (SMARCA2/4, respectively) drive chromatin remodeling activity in the BAF complex. 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 inhibition of BRM (Hoffman, 2014; Oike, 2013). However, BRG1 can also have oncogenic activity in NSCLC (Li, 2019) and can serve as a predictive biomarker for chemotherapy outcome in patients (Bell, et al 2015), rationalizing the use of a dual BRG1/BRM ATPase inhibitor (FHD286) in NSCLC patients in combination with chemotherapy. Here, we demonstrate that a panel of in vitro and in vivo NSCLC models respond to BAF ATPase inhibition as a single agent treatment, irrespective of SMARCA4 mutation status. Analysis of gene expression and dependency data suggests that FHD286 sensitivity correlates with activity of genes related to DNA damage response and repair. We furthermore demonstrate an enhancing effect on tumor growth inhibition in vitro and in vivo driven by apoptosis and cell cycle arrest when combining dual FHD286 with current first and second line standards of care. Collectively, these results indicate a path forward for the development of FHD-286, a clinical stage BRM/BRG1 ATPase inhibitor, for the treatment of NSCLC patients both as a single agent treatment and in combination with current standards of care. Citation Format: Oliver Mikse, Ammar Adam, GiNell Elliott, Dave Lahr, Victoria Amaral, Priyadharshini Viswanathan, Liv Johannessen, Hafiz Ahmad, Jessica Wan, Steven Bellon, Murphy Hentemann. FHD286 is a BRG1/BRM ATPase inhibitor showing efficacy in NSCLC models and is applicable to NSCLC patients both as a single agent treatment and in combination with current standards of care [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 A079.