Abstract 4589: Synergistic effects of EZH1/2 dual inhibition and cisplatin on lung cancer cell lines with loss of SMARCA4 and SMARCA2

Abstract

Abstract Purpose: SMARCA4 mutations are observed in approximately 10% of non-small cell lung cancer (NSCLC) cases and are implicated in various biological functions. Lung cancers harboring these mutations are associated with poor prognosis and often exhibit resistance to conventional chemotherapies, highlighting the urgent need for innovative therapeutic strategies. We evaluated the efficacy of a novel EZH1/2 dual inhibitor, HM97662, and its synergistic potential with cisplatin in SMARCA4-deficient lung cancer cell lines. Experimental Design: CCLE datasets were employed to identify cell lines harboring truncated mutations in the SMARCA4 gene. Immunoblotting was conducted to verify the inactivation of SMARCA4 and to check for the expression of SMARCA2. We assessed cellular viability and colony-forming capabilities of lung cancer cell lines (NCI-H1975, PC9, A549, HCC15, NCI-H522, NCI-H1581, NCI-H1048, NCI-H841) to determine the cytotoxic effects of an EZH1/2 dual inhibitor as well as cisplatin, both as single agents and in combination. Results: Immunoblotting showed distinct lung cancer cell lines characterized by three profiles: proficient SMARCA4 expression, absent SMARCA4 but present SMARCA2 expression, and concurrent loss of both SMARCA4 and SMARCA2. After 14 days of treatment with the EZH1/2 dual inhibitor HM97662, there was a significant reduction in cell proliferation, particularly in the both SMARCA4- and SMARCA2-loss cell lines. Furthermore, colony-forming assays demonstrated a significant decrease in colony-forming ability upon HM97662 treatment, an effect exclusive to the both SMARCA4 and SMARCA2 loss cell lines. Pre-treatment with 1 µM of HM97662 for 7 days potentiated the cytotoxicity of cisplatin compared to untreated controls in the SMARCA4/2 loss cell lines, as indicated by a lower IC50 value. Conclusion: The novel EZH1/2 dual inhibitor, HM97662, exhibits antitumor activity and a synergistic effect with cisplatin in lung cancer cell lines with concomitant loss of SMARCA4 and SMARCA2. These findings suggest the potential utility of EZH1/2 dual inhibition as a targeted therapeutic approach in lung cancers characterized by the dual loss of SMARCA4/2. Citation Format: Jeongjae Lee, Bhumsuk Keam, Soyeon Kim, Jeonghwan Youk, Miso Kim, Tae Min Kim, Dong-Wan Kim, Heo Dae Seog. Synergistic effects of EZH1/2 dual inhibition and cisplatin on lung cancer cell lines with loss of SMARCA4 and SMARCA2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4589.