Abstract 2405: NGS-based molecular profiling reveals remarkable anticancer synergy of EZH1/2 dual inhibitor HM97662 with standard-of-care therapy on small cell lung cancer

Abstract The development of EZH1/2 inhibitors is crucial in targeting tumors due to their central role in epigenetic regulation. These EZH1/2 enzymes contribute to tumorigenesis by promoting transcriptional repression of tumor suppressor genes. Studies have shown that inhibiting EZH1/2 can suppress tumor growth and improve clinical outcomes, particularly in hematological malignancies. However, the selective potency of EZH1/2 inhibitors in a limited range of solid tumors highlights the need for precise selection of indications based on molecular characteristics. Recent research has discovered that cancers with a small cell neuroendocrine (SCN) phenotype, characterized by high aggressiveness and limited treatment options, share molecular characteristics and drug susceptibility profiles with hematological malignancies. Moreover, the role of EZH2 in the cancer with SCN feature, such as small cell lung cancer (SCLC) and neuroendocrine prostate cancer (NEPC), has been increasingly recognized. Notably, EZH2 contributes to chemo-resistance in SCLC by repressing the transcription of Schlafen 11 (SLFN11), a biomarker of sensitivity to DNA-damaging chemotherapies. Inhibition of EZH2 upregulates SLFN11 expression and restores chemosensitivity in chemo-resistant SCLC models, suggesting EZH2 blockade as a promising therapeutic strategy. Previously, we evaluated antiproliferative properties of HM97662 on diverse solid cancers and demonstrated its great potential in various SCLCs. Therefore, we explored to determine the molecular factors that influence the sensitivity to HM97662 and synergism with standard-of-care (SoC) in SCLC. Using next generation sequencing (NGS), we analyzed the transcriptomic profiles of HM97662-sensitive and non-sensitive SCLC cell lines, verifying the molecular determinants of the sensitivity. We also identified the transcriptomic changes when EZH1/2 were inhibited through HM97662 in the SCLC cell lines at the gene as well as pathway level. We found that HM97662 treatment selectively increased the expression of genes involved in cell cycle regulation including CDKN1A (p21) in sensitive SCLC cell lines. Similarly, SLFN11 level was also dose-dependently increased. Remarkably, HM97662 exhibited super-synergistic effect with SoC in SCLC xenograft models, outperforming to both an EZH2 inhibitor and another EZH1/2 dual inhibitor. This study highlights the transformative potential of combining epigenetic modulation with conventional treatment regimens to overcome therapeutic limitations. Leveraging NGS, we identified molecular signatures predictive of enhanced response to the EZH1/2 dual inhibitor HM97662. These findings pave the way for personalized therapeutic strategies, offering renewed hope for patients with small cell lung cancer and other cancers with SCN feature as well. Citation Format: Gunwoo Lee, Seungheon Baek, Jungwha Park, Aran Park, Seung Hyun Jung, Jooyun Byun, Young Gil Ahn. NGS-based molecular profiling reveals remarkable anticancer synergy of EZH1/2 dual inhibitor HM97662 with standard-of-care therapy on small cell lung cancer [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 2405.