Division of Cancer Therapeutics, National Cancer Center Research InstituteAbstract国立がん研究センター研究所がん治療学研究分野― 185 ―Ovarian clear cell carcinoma is a refractory cancer for which no treatment has been established. In addition, ovarian clear cell carcinoma occurs not only in elderly patients but also in young women under the age of 50, who are of child-rearing generation, at a relatively high rate compared to other cancer types, so there is a need to establish a treatment method as soon as possible. The ARID1A gene is a constituent gene of the SWI/SNF chromatin remodeling complex and is involved in the regulation of various biological functions such as transcription and DNA repair. The ARID1A gene is frequently deficient in about 50% of ovarian clear cell carcinomas. In this study, we have identified a synthetic lethal target for ARID1A-deficient cancer, with the goal of establishing a promising synthetic lethal treatment for ARID1A-deficient ovarian clear cell carcinoma. We first analyzed a public database to analyze genetic abnormalities in ovarian cancer cell lines, and identified deubiquitinase gene X as a synthetic lethal target for ARID1A-deficient ovarian clear cell carcinoma. Next, as a result of verification using an ovarian clear cell carcinoma cell line model, it was clarified that suppression of X had little effect on survival in ARID1A-proficient cells and was lethal in ARID1A-deficient cells, that is, synthetic lethality. Furthermore, in order to investigate the antitumor effect using an in vivo model, we have established a cell line model system for drug-induced target suppression and investigated the antitumor effect in a mouse transplanted tumor model. In ARID1A-deficient cell lines, suppression of X results in degradation of growth factors, which are targets for the deubiquitination of X. It was suggested that apoptosis was induced by suppression of the STAT3 pathway as a downstream phosphorylatation signaling pathway by suppression of 難治性がんにおけるクロマチン制御因子の欠損型異常にDevelopment of synthetic lethal therapies based on chromatin regulator-deficient abnormalities in refractory 基づいた合成致死治療法の開発cancers荻原 秀明Hideaki Ogiwara
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