Abstract 3240: Synthetic lethal strategy of an EZH1/2 dual inhibitor, HM97662, for the treatment of ARID1A-mutated solid cancers
Authors: Kim Yu-Yon , Jung Seung Hyun , Han Seon Yeong , Byun Jooyun , Lee Gunwoo , Lee Miyoung , Park Junghwa , Kong Taeyeon , Han Hyesun , Lee Sang Hyun , Ahn Young Gil 
Published: March 2024

Abstract
Enhancer of zeste homolog 2 (EZH2), an enzymatic subunit of polycomb repressive complex 2 (PRC2), is known to catalyze tri-methylation of histone H3 at lysine 27 (H3K27me3), leading to repression of the transcription of its target genes involved in cell cycle regulation, cell proliferation, cell differentiation, and tumor suppression. It has been proposed that epigenetic regulators could serve as novel drug targets, and EZH2 is one of the targets with considerable therapeutic potential. Meanwhile, synthetic lethality is a phenomenon whereby individual genes in a pair can be knocked-out without affecting cell viability, while disruptions of both genes concurrently cause cell death. It has been shown that loss-of-function (LOF) mutations of component proteins in SWI-SNF chromatin remodeling complex, including PBRM1, ARID1A, SMARCA4, and so on, are synthetic lethal with inhibition of the histone methyltransferase EZH2. Especially, ARID1A-mutated solid tumors are vulnerable to EZH2 inhibition. Given that ARID1A is mutated in approximately 10% of all tumor types, inhibiting EZH2 activity could be a promising therapeutic strategy for cancer patients with this mutation. Although the methyltransferase activity of PRC2 is mainly contributed by EZH2, EZH1 also plays a compensatory role in maintaining tri-methylation of H3K27 and directly binds to chromatin, modulating its condensation. These emphasize that blocking both EZH1 and EZH2 might have greater anti-tumor effect than EZH2 alone. 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 (GOF) mutant EZH2 at nanomolar concentrations. HM97662 potently repressed tri-methylation of H3K27me3 in TOV-21G (ovarian cancer) and HT-1376 (bladder cancer) cell lines with ARID1A LOF mutation. HM97662 also showed a wide and strong growth inhibitory effect in various solid cancer cell lines harboring ARID1A mutation. HM97662 exhibited potent antitumor activities in xenograft mouse models with various ARID1A-mutated cancer cells including ovarian, bladder, small cell lung cancer, prostate, and gastric cancers (e.g. TOV-21G, HT-1197, NCI-H128, LNCap, and MKN-45, respectively). Once-daily oral dosing of HM97662 greatly inhibited tumor growth in a dose-dependent manner without significant clinical signs compared to known EZH2 selective or EZH1/2 dual inhibitors. HM97662 also exhibited a synergistic effect in combination with second-line standard of care in small cell lung cancer. In conclusion, these preclinical studies demonstrated that HM97662 as an EZH1/2 dual inhibitor, holds promising therapeutic potential for ARID1A-mutated solid cancers. It is crucial to evaluate the effectiveness of HM97662 in subsequent clinical trials.
Citation Format: Yu-Yon Kim, Seung Hyun Jung, Seon Yeong Han, Jooyun Byun, Gunwoo Lee, Miyoung Lee, Junghwa Park, Taeyeon Kong, Hyesun Han, Sang Hyun Lee, Young Gil Ahn. Synthetic lethal strategy of an EZH1/2 dual inhibitor, HM97662, for the treatment of ARID1A-mutated solid cancers [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 3240.