DGKA Provides Platinum Resistance in Ovarian Cancer Through Activation of c-JUN–WEE1 Signaling

作者：Jie Li, Chaoyun Pan, Austin C. Boese, JiHoon Kang, Anna D. Umano, Kelly R. Magliocca, Wenqing Yang, Yu Zhang, Sagar Lonial, Lingtao Jin, Sumin Kang · 发表于：Clinical Cancer Research · 年份：2020 · DOI：10.1158/1078-0432.ccr-19-3790 · 被引用次数：62 · 研究领域：Microtubule and mitosis dynamics、PI3K/AKT/mTOR signaling in cancer、RNA Research and Splicing

PURPOSE: Although platinum compounds are the first-line treatment for ovarian cancer, the majority of patients relapse and develop resistance to treatment. However, the mechanism underlying resistance is unclear. The goal of our study is to decipher the mechanism by which a metabolic kinase, diacylglycerol kinase alpha (DGKA), confers platinum resistance in ovarian cancer. EXPERIMENTAL DESIGN: Metabolic kinase RNAi synthetic lethal screening was used to identify a cisplatin resistance driver in ovarian cancer. DGKA variants were used to demonstrate the need for DGKA activity in cisplatin resistance. Phospho-proteomic and genomic screens were performed to identify downstream effectors of DGKA. Therapeutic efficacy of targeting DGKA was confirmed and clinical relevance of DGKA signaling was validated using ovarian cancer patient-derived tumors that had different responses to platinum-based therapy. RESULTS: We found that platinum resistance was mediated by DGKA and its product, phosphatidic acid (PA), in ovarian cancer. Proteomic and genomic screens revealed that DGKA activates the transcription factor c-JUN and consequently enhances expression of a cell-cycle regulator, WEE1. Mechanistically, PA facilitates c-JUN N-terminal kinase recruitment to c-JUN and its nuclear localization, leading to c-JUN activation upon cisplatin exposure. Pharmacologic inhibition of DGKA sensitized ovarian cancer cells to cisplatin treatment and DGKA-c-JUN-WEE1 signaling positively correlated with p...