O05_06

Exploring cancer treatment candidates targeting chromatin remodeling factors

Reiko WATANABE *¹, Junsoo SONG¹, Ui AYAKO², Mizuguchi KENJI¹

¹Laboratory for Computational Biology, Institute for Protein Research, Osaka University
²Institute of Development, Aging and Cancer, Tohoku University
( * E-mail: reiko-watanabe@protein.osaka-u.ac.jp)

The SWI/SNF chromatin-remodeling family comprises various protein complexes that regulate gene expression during cellular development and influence the DNA damage response in an ATP- and complex-dependent manner. Recent genome sequencing of various cancer cells has revealed frequent mutations in SWI/SNF components, particularly in ARID1A, a variant subunit in the BRG1-associated factor (BAF) complex of the SWI/SNF family. ARID1A mutations or loss of function are commonly observed in several cancers, including ovarian, endometrial, and gastric cancers, and are contributing to cancer development by disrupting normal cell growth regulation, promoting genomic instability, and enhancing tumor progression. In this study, we aimed to explore potential therapeutic targets for cancer treatment based on two strategies. First, we proposed an innovative patient stratification strategy considering both ARID1A protein expression level and its function and identified differentially expressed genes (DEGs) between groups. Our method highlights transcriptional variations of tumor immune microenvironment, which were hard to detect with stratification based on only mutation information. Second, synthetic lethality (SL) was considered to search potential therapeutic targets. Drugs targeting SL partners of ARID1A could potentially treat cancers with ARID1A loss while sparing normal cells. Although many wet-lab methods have been developed to screen for SL pairs, the number of known SL pairs is currently a very small fraction of all candidate pairs due to the large number of human gene combinations. By using computational prediction tools that can effectively reduce the search space for SL pairs, potential SL pairs for ARID1A were collected and screened based on prognosis in tumor patients. These approaches can propose potential targets in cancer therapeutics and by integrating molecular stratification and synthetic lethality strategies, it can be possible to develop more effective and less toxic therapeutic interventions tailored to the specific genetic makeup of cancer patients.