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

Autor:	Kinose Y; Penn Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA., Xu H; Penn Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA., Kim H; Penn Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA., Kumar S; Penn Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA., Shan X; Penn Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA., George E; Penn Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA., Wang X; Penn Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA., Medvedev S; Penn Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA., Ferman B; Penn Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA., Gitto SB; Penn Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA.; Department of Pathology and Laboratory Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Whicker M; Penn Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA., D'Andrea K; Department of Medicine, Division of Translational Medicine and Human Genetics, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Wubbenhorst B; Department of Medicine, Division of Translational Medicine and Human Genetics, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Hallberg D; The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD., O'Connor M; AstraZeneca, R&D Oncology, Cambridge, United Kingdom., Schwartz LE; Department of Pathology, Hospital of the University of Pennsylvania, Philadelphia, PA 19104., Hwang WT; Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA 19104, USA., Nathanson KL; Department of Medicine, Division of Translational Medicine and Human Genetics, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Mills GB; Division of Oncological Sciences Knight Cancer Institute, Oregon Health and Science University, Portland, OR., Velculescu VE; The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD., Wang TL; The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD., Brown EJ; Department of Cancer Biology and the Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Drapkin R; Penn Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA., Simpkins F; Penn Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA.
Jazyk:	angličtina
Zdroj:	Research square [Res Sq] 2023 Sep 27. Date of Electronic Publication: 2023 Sep 27.
DOI:	10.21203/rs.3.rs-3314138/v1
Abstrakt:	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. Competing Interests: Conflict of Interest F.S. serves on scientific advisory boards for AstraZeneca, GSK and Zentalis Pharmaceuticals. She has received institutional research funding from AstraZeneca, Repare Therapeutics, Instill Bio and Sierra Oncology. G.B.M. receives support or acts as a consultant for Amphista, Astex, AstraZeneca, BlueDot, Chrysallis Biotechnology, Ellipses Pharma, GSK, ImmunoMET, Infinity, Ionis, Leapfrog Bio, Lilly, Medacorp, Nanostring, Nuvectis, PDX Pharmaceuticals, Qureator, Roche, Rybodyne, Signalchem Lifesciences, Tarveda, Turbine, and Zentalis Pharmaceuticals has stock options with Bluedot, Biodyne, Catena Pharmaceuticals, ImmunoMet, Nuvectis, RyboDyne, SignalChem, Tarveda, and Turbine, has transferred technology to Myriad and Nanostring and receives sponsored research support from AstraZeneca Nanostring and Zentalis. E.J.B. serves on the scientific advisory board of Atrin Pharmaceuticals and has been an advisor for Sierra Oncology. R.D. serves on the scientific advisory board of Repare Therapeutics and Siamab Therapeutics and advises Mersana Therapeutics and nVision Medical.
Databáze:	MEDLINE
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