Abstract LB310: Methylation synthetic lethality: <i>SMARCA1</i> methylation and inhibition of pyrimidine synthesis

Abstract Synthetic lethality is a promising therapeutic strategy, but the number of combinations of a mutated gene and a therapeutic target gene is limited. In contrast with a mutation, DNA methylation is frequently present in many types of cancers, and can be a rich source 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]. We have been searching to identify a novel synthetic lethal combinations by using methylated genes. In this study, as a methylated gene, we focused on SMARCA1, which was often methylated in various types of cancers [Takeshima et al., Cancer Lett, 357:328-338, 2015], and encodes a ISWI-type chromatin remodeling factor. Genes lethal for cancer cell lines with SMARCA1 low expression were screened for using the sgRNA screening database [DepMap], and two of top 3 candidate genes identified were genes related to pyrimidine biosynthesis pathway, DHODH and UMPS. To experimentally validate the usefulness of this combination, five SMARCA1-methylated and seven -unmethylated cell lines were treated with a DHODH inhibitor, and SMARCA1-methylated cell lines showed higher sensitivity. These cell lines included three cell lines not used in the screening, validating the usefulness of the combination. Sensitivity to DHODH inhibition in SMARCA1-methylated cell line, RKO, was reduced by exogenous overexpression of SMARCA1, indicating the causal role of SMARCA1 methylation for the synthetic lethality. We are now evaluating in vivo usefulness of this combination. These results showed that DNA methylation is a rich source for a synthetic lethality, and the inhibition of pyrimidine synthesis is a promising therapeutic strategy for SMARCA1-methylated cancers. Citation Format: Hideyuki Takeshima, Yui Ohashi, Ryoma Mashiko, Toshikazu Ushijima. Methylation synthetic lethality: SMARCA1 methylation and inhibition of pyrimidine synthesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB310.