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

Yasuto Kinose; Haineng Xu; Hyoung Kim; Sushil Kumar; Xiaoyin Shan; Erin George; Xiaolei Wang; Sergey Medvedev; Benjamin Ferman; Sarah B Gitto; Margaret Whicker; Kurt D'Andrea; Bradley Wubbenhorst; Dorothy Hallberg; Mark O'Connor; Lauren E Schwartz; Wei-Ting Hwang; Katherine L Nathanson; Gordon B Mills; Victor E Velculescu; Tian-Li Wang; Eric J Brown; Ronny Drapkin; Fiona Simpkins

doi:10.21203/rs.3.rs-3314138/v1

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

Res Sq [Preprint]. 2023 Sep 27:rs.3.rs-3314138. doi: 10.21203/rs.3.rs-3314138/v1.

Authors

Yasuto Kinose^{1

2}, Haineng Xu^{1

2}, Hyoung Kim^{1

2}, Sushil Kumar^{1

2}, Xiaoyin Shan^{1

2}, Erin George^{1

2}, Xiaolei Wang^{1

2}, Sergey Medvedev^{1

2}, Benjamin Ferman^{1

2}, Sarah B Gitto^{1

2

3}, Margaret Whicker^{1

2}, Kurt D'Andrea⁴, Bradley Wubbenhorst⁴, Dorothy Hallberg⁵, Mark O'Connor⁶, Lauren E Schwartz⁷, Wei-Ting Hwang⁸, Katherine L Nathanson⁴, Gordon B Mills⁹, Victor E Velculescu⁵, Tian-Li Wang⁵, Eric J Brown¹⁰, Ronny Drapkin^{1

2}, Fiona Simpkins^{1

2}

Affiliations

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.
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.

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 ARID1A^MUT but not ARID1A^WT 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 ARID1A^MUT 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.

Keywords: ARID1A; ATR; BRD4; DNA damage response; WEE1; clear cell ovarian cancer.

Publication types

Preprint

Abstract

Publication types

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