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Clin Cancer Res. 2018 Jul 1;24(13):3163-3175. doi: 10.1158/1078-0432.CCR-18-0204. Epub 2018 Apr 3.

An Effective Epigenetic-PARP Inhibitor Combination Therapy for Breast and Ovarian Cancers Independent of BRCA Mutations.

Author information

1
Molecular and Cellular Biochemistry Department, Indiana University, Bloomington, Indiana.
2
Medical Sciences Program, Indiana University School of Medicine, Bloomington, Indiana.
3
Department of Radiation Oncology, School of Medicine, University of Maryland, Baltimore, Maryland.
4
Astex Pharmaceuticals, Inc., Pleasanton, California.
5
Astex Therapeutics Limited, Cambridge, United Kingdom.
6
Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland.
7
Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
8
Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana.
9
Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
10
Molecular and Cellular Biochemistry Department, Indiana University, Bloomington, Indiana. knephew@indiana.edu.
11
Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana.
12
Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, Indiana.

Abstract

Purpose: PARP inhibitors (PARPi) are primarily effective against BRCA1/2-mutated breast and ovarian cancers, but resistance due to reversion of mutated BRCA1/2 and other mechanisms is common. Based on previous reports demonstrating a functional role for DNMT1 in DNA repair and our previous studies demonstrating an ability of DNA methyltransferase inhibitor (DNMTi) to resensitize tumors to primary therapies, we hypothesized that combining a DNMTi with PARPi would sensitize PARPi-resistant breast and ovarian cancers to PARPi therapy, independent of BRCA status.Experimental Design: Breast and ovarian cancer cell lines (BRCA-wild-type/mutant) were treated with PARPi talazoparib and DNMTi guadecitabine. Effects on cell survival, ROS accumulation, and cAMP levels were examined. In vivo, mice bearing either BRCA-proficient breast or ovarian cancer cells were treated with talazoparib and guadecitabine, alone or in combination. Tumor progression, gene expression, and overall survival were analyzed.Results: Combination of guadecitabine and talazoparib synergized to enhance PARPi efficacy, irrespective of BRCA mutation status. Coadministration of guadecitabine with talazoparib increased accumulation of ROS, promoted PARP activation, and further sensitized, in a cAMP/PKA-dependent manner, breast and ovarian cancer cells to PARPi. In addition, DNMTi enhanced PARP "trapping" by talazoparib. Guadecitabine plus talazoparib decreased xenograft tumor growth and increased overall survival in BRCA-proficient high-grade serous ovarian and triple-negative breast cancer models.Conclusions: The novel combination of the next-generation DNMTi guadecitabine and the first-in-class PARPi talazoparib inhibited breast and ovarian cancers harboring either wild-type- or mutant-BRCA, supporting further clinical exploration of this drug combination in PARPi-resistant cancers. Clin Cancer Res; 24(13); 3163-75. ©2018 AACR.

PMID:
29615458
DOI:
10.1158/1078-0432.CCR-18-0204
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