Abstract 6270: Combination therapy with selective SMARCA2 (BRM) degraders for treatment of SMARCA4 (BRG1)-deficient cancers
Authors: Hulse Michael , Elkins Margot , Burtell Jessica , Vykuntam Komali , Vaddi Kris , Combs Andrew , Ito Koichi , Scherle Peggy 
Published: June 2023

Abstract
SMARCA2 (BRM) and SMARCA4 (BRG1) are mutually exclusive core catalytic subunits of the SWI/SNF complexes and use their ATPase domain to regulate the composition of nucleosomes. Between 4-5% of Non-Small Cell Lung Cancer (NSCLC) patients harbor SMARCA4 damaging mutations or SMARCA4 homo-deletions, resulting in loss of SMARCA4 protein expression. These SMARCA4-deleted cancer cells are predicted to be highly dependent on the paralog gene SMARCA2 for their survival. Therefore, targeting SMARCA2 in SMARCA4-deleted cancers using selective SMARCA2 degraders induces synthetic lethality while sparing SMARCA4 wild type normal cells. Although the treatment of lung cancer has improved considerably in recent years with the development of immune checkpoint inhibitors (ICIs) and specific KRASG12C covalent inhibitors, KRASG12C mutations significantly co-occur in 15-17% of SMARCA4-deleted NSCLC patients and have also been shown to correlate with a worse clinical outcome. The co-occurrence of KRASG12C/SMARCA4-deletion mutations in NSCLC led us to investigate whether combining our selective SMARCA2 degraders with KRASG12C or other MAPK pathway inhibitors would demonstrate synergistic effects. To test this hypothesis, we treated SMARCA4 damaging/low expression KRASG12C mutant cell lines with our SMARCA2 degraders and several KRASG12C inhibitors, in addition to SHP2 and MEK inhibitors. Robust synergy was observed with these combinations, suggesting that targeting SMARCA2 together with agents that inhibit distinct nodes of the MAPK pathway in patients with SMARCA4-deleted cancer may be a promising therapeutic strategy. To further understand the mechanisms underpinning the synergy between our SMARCA2 degraders and KRASG12C/MAPK pathway inhibitors, we conducted RNA-seq and found unique transcriptional signatures in the synergistic combinations relative to those of either agent alone. We are currently testing if this in vitro synergy with our SMARCA2 degraders extends to in vivo combination efficacy in CDX and PDX models. Furthermore, early data suggested that SMARCA4 deletion may indicate poor outcomes of ICIs in lung cancer patients. Interestingly, our SMARCA2 degraders promote the antigen presentation pathway and induce pro-inflammatory cytokine expression in SMARCA4-deleted cancer cells. We are currently investigating combinations of our SMARCA2 degraders with ICIs using syngeneic mouse models and human ex-vivo approaches. In summary, our preclinical data suggest that potent and selective SMARCA2 targeted degraders may potentially improve patient outcomes when combined with therapeutic agents targeting the RAS/MAPK pathway and/or ICIs in SMARCA4-deleted cancers. The combination of SMARCA2 degraders with standard of care agents warrants further investigation as a potential novel, effective, and highly targeted combination approach.
Citation Format: Michael Hulse, Margot Elkins, Jessica Burtell, Komali Vykuntam, Kris Vaddi, Andrew Combs, Koichi Ito, Peggy Scherle. Combination therapy with selective SMARCA2 (BRM) degraders for treatment of SMARCA4 (BRG1)-deficient cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6270.