Fiona Simpkins, Yasuto Kinose, Haineng Xu, Hyoung Kim, Sushil Kumar, Xiaoyin Shan, Erin Geroge, Xiaolei Wang, Sergey Medvedev, Benjamin Ferman, Sarah Gitto, Margaret Whicker, Kurt D Andrea, Bradley Wubbenhorst, Dorothy Hallberg, Mark O'Connor, Lauren Schwartz, Wei-Ting Hwang, Katherine Nathanson, Gordon Mills, Victor Velculescu, Tian-Li Wang, Eric Brown, Ronny Drapkin
ARID1A , an epigenetic tumor suppressor, is the most common gene mutation in clear-cell ovarian cancers (CCOCs). CCOCs are often resistant to standard chemotherapy and lack effective therapies. We hypothesized that ARID1A loss would increase CCOC cell dependency on chromatin remodeling and DNA repair pathways for survival. We demonstrate that combining BRD4 inhibitor (BRD4i) with DNA damage response inhibitors (ATR or WEE1 inhibitors; e.g. BRD4i-ATRi) was synergistic at low doses leading to decreased survival, and colony formation in CCOC in an ARID1A dependent manner...
September 27, 2023: Research Square