Abstract 1681: Strong synergistic activity of an EZH1/2 dual inhibitor, HM97662, in combination with standard chemotherapy in preclinical models of advanced solid tumors

Abstract Many cancer patients eventually develop resistance to chemotherapy drugs after treatment. For instance, platinum-based drugs are commonly used as first-line treatments for ovarian cancer. While many patients initially respond well to this therapy, approximately 80% experience tumor recurrence within two years and ultimately acquire platinum-resistance. Recent studies have shown that EZH2 plays a role in regulating cisplatin resistance in ovarian cancer. As a similar example, small cell lung cancer (SCLC) is aggressive with poor prognosis, particularly in relapsed or refractory cases. While irinotecan is commonly used as 2nd-line therapy due to its manageable toxicity and efficacy, its effectiveness as a monotherapy is limited by chemotherapy resistance. Preclinical studies suggest that combining EZH2 inhibitors with chemotherapy may enhance anticancer efficacy by modulating the epigenetic environment and disrupting DNA repair mechanisms. This combination holds promise for overcoming resistance and improving outcomes in SCLC and other cancers. EZH2, an enzymatic subunit of the polycomb repressive complex 2 (PRC2), catalyzes the tri-methylation of histone H3 at lysine 27 (H3K27me3), repressing target genes involved in cell cycle regulation, differentiation, and tumor suppression. EZH2 and SWI/SNF have opposing roles in chromatin regulation, and EZH2 overexpression is linked to SWI/SNF mutations. This interaction affects cancer cell survival, highlighting EZH2 as a critical therapeutic target. Dual inhibition of EZH1 and EZH2 may offer greater anti-tumor efficacy, as EZH1 can compensate for the loss of EZH2 activity. Herein, we introduce a novel EZH1/2 dual inhibitor, HM97662, which concurrently suppressed the methyltransferase activity not only wild-type EZH1, but also wild-type and gain of function mutant EZH2 at nanomolar concentrations. HM97662 potently repressed tri-methylation of H3K27me3 in cancer cell lines. HM97662 also showed a wide and strong growth inhibitory effect in various solid cancer cell lines. Moreover, HM97662 exhibited potent antitumor activities in xenograft mouse models with various solid cancer cells including ovarian, bladder, small cell lung cancer, and gastric cancers. Additionally, HM97662 showed synergistic effects with chemotherapies such as topoisomerase inhibitors and platinum-based standard treatment in those xenograft models. These results suggest that concurrent treatment with HM97662 and chemotherapy enhances in vivo tumor regression at well-tolerated doses. In conclusion, this preclinical study demonstrated that HM97662, an EZH1/2 dual inhibitor, has promising therapeutic potential against advanced solid tumors, either alone or in combination with standard-of-care cytotoxic agents. It is urgent to assess the effectiveness of HM97662 in further clinical trials. Citation Format: Seon Yeong Han, Gunwoo Lee, Aran Park, Seung Hyun Jung, Jooyun Byun, Young Gil Ahn. Strong synergistic activity of an EZH1/2 dual inhibitor, HM97662, in combination with standard chemotherapy in preclinical models of advanced solid tumors [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 1681.