Abstract 7055: Synergistic effects of HM97662 as an EZH1/2 dual inhibitor combined with DNA-damaging agents on malignant lung cancers harboring SMARCA4-deficiency.

Abstract EZH (enhancer of zeste homolog) is a histone methyltransferase that catalyzes the trimethylation of H3K27 and functions as a catalytic subunit of the polycomb repressive complex 2 (PRC2). Through epigenetic regulation, EZH modulates the transcription of tumor suppressor genes, thereby contributing to cancer cell survival, proliferation, metastasis, and drug resistance. In particular, the enzymatic activity of EZH2 is strongly associated with poor clinical outcomes, indicating that EZH2 has high therapeutic potential in cancer treatment. Under normal conditions, EZH1 and EZH2 function complementarily to support PRC2 and maintain epigenomic homeostasis. However, inhibiting EZH2 alone can trigger compensatory activation of EZH1, reducing benefit and enabling resistance. Thus, dual inhibition of EZH1 and EZH2 is a rational strategy to overcome resistance via broad PRC2 suppression across the tumor microenvironment. Thoracic SMARCA4-deficient undifferentiated tumor (TSDUT) which has been classified in 2021 by World Health Organization (WHO) at first, is a newly defined, high-grade malignancy with undifferentiated/rhabdoid features, marked aggressiveness, and poor prognosis. It is molecularly characterized by SMARCA4 deficiency or concurrent loss of SMARCA2, which are key subunits of the SWI/SNF complex that are often mutated and show synthetical lethal relationships in various cancers. Owing to its rarity and histological heterogeneity, diagnosis is challenging, and standard treatments are lacking; TSDUT frequently recurs after surgery, shows radio-resistance, and responds poorly to chemotherapy. Notably, EZH1/2 inhibition may enhance SLFN11-mediated sensitivity to DNA-damaging agents, offering a promising therapeutic avenue through combination. 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. Furthermore, HM97662 demonstrated robust antitumor efficacy in DMS114 and SBC-5 xenograft mouse models of multiple SMARCA4-deficient cancers, including TSDUT. HM97662 synergized with chemotherapies especially topoisomerase 1 inhibitors and other DNA-damaging agents. Collectively, these findings indicate that combining HM97662 with DNA-damaging agents can drive enhanced in vivo tumor regression at well-tolerated doses in malignant lung cancers. 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 DNA-damaging agents. HM97662 is currently underway in a Phase 1 clinical trial, and these results will further support its clinical development. Citation Format: Seung Hyun Jung, Jaeyul Choi, Aran Park, Seungheon Baek, Jooyun Byun, Young Gil Ahn. Synergistic effects of HM97662 as an EZH1/2 dual inhibitor combined with DNA-damaging agents on malignant lung cancers harboring SMARCA4-deficiency 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 7055.