Abstract 6505: Combination therapy with selective SMARCA2 (BRM) inhibitor HD-11273 for treatment of SMARCA4 (BRG1)-deficient cancers

Abstract SMARCA2 (BRM) and SMARCA4 (BRG1) are the catalytic subunits of SWI/SNF chromatin remodeling complexes, functioning in a mutually exclusive manner to regulate nucleosome composition via their ATPase domains. Pan-cancer analysis indicates that SMARCA4 mutations occur at all cancers, in particular, SMARCA4 mutations are found in 8-10% of non-small cell lung cancer (NSCLC) cases, suggesting SMARCA2 as a potential synthetic lethal target. Several studies reported that the co-mutation frequency of KRAS and SMARCA4 in NSCLC is approximately 7.7-10%, with about 39-47% of these SMARCA4-mutant patients harboring KRAS mutations. And patients with SMARCA4-mutant NSCLC generally demonstrate poor responses to conventional chemotherapy. We selected HD-11273 as a preclinical candidate, which showed improved physicochemical properties through the preparation of a specific salt of HD-10991, a selective SMARCA2 inhibitor. Here, we report a combination study of HD-11273 with standard chemotherapy and KRAS inhibitors currently in development. HD-11273 monotherapy significantly inhibited growth of SMARCA4-del A549 CDX model as well as patient derived cancer organoid (PDO) models. Combination therapies targeting multiple pathways are considered essential for overcoming monotherapy limitations, including resistance arising from prolonged treatment. To evaluate the therapeutic benefit, we tested our selective SMARCA2 inhibitor in combination with KRASG12C (storasib, adagrasib), KRASG12D (RMC9805), and pan-KRAS (Draxonrasib) inhibitors in cancers harboring KRAS and SMARCA4 co-mutations. Each combination exhibited robust synergy, suggesting that dual targeting of SMARCA2 and KRAS could be a promising therapeutic strategy. Additionally, we investigated the combinatory effect of a SMARCA2 inhibitor with standard chemotherapy agents for NSCLC; combination with oxaliplatin, docetaxel, or pemetrexed showed partial synergy, indicating that SMARCA2 inhibitors may serve as promising candidates for combination chemotherapy. In conclusion, the combination of HD-11273 with KRAS targeted therapy showed synergistic anti-tumor effect in preclinical models of SMARCA4 and KRAS co-mutated NSCLC. Also, the combination of HD-11273 with standard care for NSCLC chemotherapy significantly enhances anti-tumor activity in preclinical models of SMARCA4-mutated NSCLC. Citation Format: Hyuntae Kim, MinOu Choi, Jongwoo Park, Goeun Yang, Min-Ah Park, Hyo Sun Choi, Yukyung Kim, Doo-Young Kim, Daehoon Kim, Seong Heon Kim, Suk Ho Lee. Combination therapy with selective SMARCA2 (BRM) inhibitor HD-11273 for treatment of SMARCA4 (BRG1)-deficient cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6505.