Abstract 4849: MYC-mediated resistance to immune activation by SWI/SNF mutation or chemical inhibition

Abstract ARID1A is a critical subunit of the SWI/SNF chromatin remodeling complex, frequently mutated in several cancers. We have shown that loss of ARID1A induces an accumulation of R-loops, leading to cytosolic release of RNA:DNA hybrids and single stranded DNA (ssDNA) and cGAS/STING-dependent activation of Type I interferon (IFN-I) stimulated genes (ISGs). SWI/SNF ATPase inhibitors (FHD-286, BRD98, and BRM014) and degraders (ACBI1) similarly induce ISGs through a cGAS/STING-dependent mechanism. Consequently, ARID1A mutant tumors are more highly infiltrated with cytotoxic CD8+ T cells and exhibited enhanced tumor immunity and sensitivity to immune checkpoint blockade (ICB)1. These results provide a molecular mechanism for the enrichment of ARID1A mutations among ICB responders. However, co-occurring oncogenic mutations in ARID1A mutant cancers, such as MYC, KRAS, and β-catenin, have been associated with immunosuppression in some cases through suppression of IFN-I signaling and ISG expression. It is not known how such co-occurring mutations affect the ARID1A mutant ISG response or whether such mutations would counteract ISG activation by SWI/SNF inhibitors. In this study, we investigate the impact of MYC overexpression on IFN-I responses induced by ARID1A loss or SWI/SNF inhibition in cancer cells. Our data reveal that MYC overexpression impairs the ability of these cells to induce IFN-I response genes (ISGs) when cells are directly stimulated with IFN-I or treated with inhibitors targeting the SWI/SNF complex, including FHD-286 and BRM014. Through bulk RNA-seq, we characterize the molecular mechanisms underlying this resistance, with a focus on IFN-I related genes. This study highlights the suppressive effect of MYC overexpression on IFN-I responses in ARID1A-deficient cancers and suggests a potential link to therapeutic resistance in MYC-high tumors. While the precise molecular mechanisms remain to be fully elucidated, these findings provide a foundation for future studies aimed at understanding the interplay between oncogenic drivers and immune signaling pathways, with implications for developing more effective therapeutic strategies. Reference: (1). Maxwell, M. B., et al. ARID1A Suppresses R-Loop-Mediated STING-Type I Interferon Pathway Activation of Anti-Tumor Immunity. Cell 2024, S0092867424004513. https://doi.org/10.1016/j.cell.2024.04.025. Citation Format: Shitian Li, Diana Hargreaves. MYC-mediated resistance to immune activation by SWI/SNF mutation or chemical inhibition [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 4849.