Affordable Access

Publisher Website

Dual blockade of BRD4 and ATR/WEE1 pathways exploits ARID1A loss in clear cell ovarian cancer.

Authors
  • Kinose, Yasuto1, 2
  • Xu, Haineng1, 2
  • Kim, Hyoung1, 2
  • Kumar, Sushil1, 2
  • Shan, Xiaoyin1, 2
  • George, Erin1, 2
  • Wang, Xiaolei1, 2
  • Medvedev, Sergey1, 2
  • Ferman, Benjamin1, 2
  • Gitto, Sarah B1, 2, 3
  • Whicker, Margaret1, 2
  • D'Andrea, Kurt4
  • Wubbenhorst, Bradley4
  • Hallberg, Dorothy5
  • O'Connor, Mark6
  • Schwartz, Lauren E7
  • Hwang, Wei-Ting8
  • Nathanson, Katherine L4
  • Mills, Gordon B9
  • Velculescu, Victor E5
  • And 4 more
  • 1 Penn Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
  • 2 Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA.
  • 3 Department of Pathology and Laboratory Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • 4 Department of Medicine, Division of Translational Medicine and Human Genetics, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 5 The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD.
  • 6 AstraZeneca, R&D Oncology, Cambridge, United Kingdom. , (United Kingdom)
  • 7 Department of Pathology, Hospital of the University of Pennsylvania, Philadelphia, PA 19104.
  • 8 Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 9 Division of Oncological Sciences Knight Cancer Institute, Oregon Health and Science University, Portland, OR.
  • 10 Department of Cancer Biology and the Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Type
Published Article
Journal
Research square
Publication Date
Sep 27, 2023
Identifiers
DOI: 10.21203/rs.3.rs-3314138/v1
PMID: 37841875
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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. BRD4i-ATRi caused significant tumor regression and increased overall survival in ARID1AMUT but not ARID1AWT patient-derived xenografts. Combination BRD4i-ATRi significantly increased γH2AX, and decreased RAD51 foci and BRCA1 expression, suggesting decreased ability to repair DNA double-strand-breaks (DSBs) by homologous-recombination in ARID1AMUT cells, and these effects were greater than monotherapies. These studies demonstrate BRD4i-ATRi is an effective treatment strategy that capitalizes on synthetic lethality with ARID1A loss in CCOC.

Report this publication

Statistics

Seen <100 times