Abstract 6015: Methylation synthetic lethality: CHFR methylation and KRAS inhibition in gastric cancers

Abstract

Synthetic lethality is a promising therapeutic strategy, but the number of founder mutations is limited. In contrast, DNA methylation is frequently present in many types of cancers, and can be a potential target for a synthetic lethality. So far, BRCA1 methylation with a PARP inhibitor is known as a synthetic lethality [Kawachi et al., Breast Cancer Res Treat, 181:323-329, 2020]. In this study, we aimed to identify a novel methylation synthetic lethal combination in gastric cancers. Founder methylation was searched for in 8,008 genes with putative promoter CpG islands (CGIs), and 137 genes which were 1) heavily methylated and 2) frequently methylated in primary gastric cancers (10 or more of 50 cases) were selected. The association analysis between DNA methylation and gene expression showed that 10 of 137 genes were completely silenced in gastric cancer cell lines with methylation of their promoter CGIs, but were expressed in those without. Among these 10 genes, we focused on CHFR, a known tumor-suppressor gene in gastrointestinal cancers, and genes lethal for CHFR methylation were screened for using the sgRNA screening database (The Cancer Dependency Map, DepMap). Comparison of gene dependencies of 17,645 genes between four cell lines with CHFR methylation and 12 cell lines without revealed that knockout of KRAS reduced cell growth specifically in cell lines with methylation. This synthetic lethality could be experimentally confirmed in two cell lines with CHFR methylation, AGS and 44As3, and three cell lines without, HSC41, HSC42, and MKN74. These cell lines included those not used in the screening, validating the usefulness of the combination. These results showed that gastric cancers with CHFR methylation were sensitive to KRAS inhibition, and that methylation synthetic lethality is a promising therapeutic strategy. Citation Format: Hideyuki Takeshima, Takahiro Ebata, Yumi Furuichi, Satoshi Yamashita, Toshikazu Ushijima. Methylation synthetic lethality: CHFR methylation and KRAS inhibition in gastric cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6015.