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PARP inhibitors: Clinical utility and possibilities of overcoming resistance.

Authors
  • Bitler, Benjamin G1
  • Watson, Zachary L2
  • Wheeler, Lindsay J3
  • Behbakht, Kian4
  • 1 Division of Reproductive Sciences, Department of Obstetrics and Gynecology, The University of Colorado, Aurora, CO, United States. Electronic address: [email protected] , (United States)
  • 2 Division of Reproductive Sciences, Department of Obstetrics and Gynecology, The University of Colorado, Aurora, CO, United States. , (United States)
  • 3 Division of Reproductive Sciences, Department of Obstetrics and Gynecology, The University of Colorado, Aurora, CO, United States; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The University of Colorado, Aurora, CO, United States. , (United States)
  • 4 Division of Reproductive Sciences, Department of Obstetrics and Gynecology, The University of Colorado, Aurora, CO, United States; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The University of Colorado, Aurora, CO, United States. Electronic address: [email protected] , (United States)
Type
Published Article
Journal
Gynecologic Oncology
Publisher
Elsevier
Publication Date
Dec 01, 2017
Volume
147
Issue
3
Pages
695–704
Identifiers
DOI: 10.1016/j.ygyno.2017.10.003
PMID: 29037806
Source
Medline
Keywords
License
Unknown

Abstract

PARP inhibitors represent a major breakthrough in ovarian cancer care. Almost half of all ovarian cancers have deficiencies in the homologous recombination (HR) DNA repair pathway, namely BRCA1/2 mutations. Given the limited therapeutic options for recurrent ovarian cancer patients there has been a significant effort to develop novel therapies to exploit DNA repair deficiencies. In 2005 and 2006, inhibiting PARP enzymes was first observed to be highly effective against cancers with HR deficiencies. PARP inhibitors are being utilized in the clinic to manage recurrent ovarian cancers that display defects in the HR repair pathway. However, PARP inhibitors also show significant clinical benefit in patients without HR deficiencies. There are currently three FDA-approved PARP inhibitors for recurrent ovarian cancer and an additional two PARP inhibitors being evaluated in late stage clinical trials. Given the expanding clinical use of PARP inhibitors and the high likelihood of acquired resistance, there is a significant need for clinical strategies to manage PARP inhibitor resistant disease. This review will examine PARP inhibitors in the context of: indications and toxicities, novel biomarkers to predict response, targeted-therapy resistance, and potential approaches to manage resistant disease.

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