PARP inhibitor resistance in ovarian cancer: Underlying mechanisms and therapeutic approaches targeting the ATR/CHK1 pathway.

Abstract

Ovarian cancer (OC) constitutes the most common cause of gynecologic cancer-related death in women worldwide. Despite consistent developments in treatment strategies for OC, the management of advanced-stage disease remains a significant challenge. Recent improvements in targeted treatments based on poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) have provided invaluable benefits to patients with OC. Unfortunately, numerous patients do not respond to PARPi due to intrinsic resistance or acquisition of resistance. Here, we discuss mechanisms of resistance to PARPi that have specifically emerged in OC including increased drug efflux, restoration of HR repair, re-establishment of replication fork stability, reduced PARP1 trapping, abnormalities in PARP signaling, and less common pathways associated with alternative DNA sensing and repair pathways. Elucidation of the precise mechanisms is essential for the development of novel strategies to re-sensitize OC cells to PARPi agents. Additionally, novel potential concepts for preventing and combating resistance to PARPi under development and relevant clinical reports on treatment strategies have been reviewed, with emphasis on the exploitation of the ATR/CHK1 kinase pathway in sensitization to PARPi to overcome resistance-induced vulnerability in ovarian cancer.

• Authors: Łukasz Biegała, Arkadiusz Gajek, Agnieszka Marczak, Aneta Rogalska
• Journal: Biochimica et biophysica acta. Reviews on cancer (Biochim Biophys Acta Rev Cancer) Vol. 1876 Issue 2 Pg. 188633 (12 2021) ISSN: 1879-2561 [Electronic] Netherlands
• PMID: 34619333 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Poly(ADP-ribose) Polymerase Inhibitors
• ATR protein, human
• Ataxia Telangiectasia Mutated Proteins
• Checkpoint Kinase 1

Topics

• Ataxia Telangiectasia Mutated Proteins (metabolism)
• Checkpoint Kinase 1 (metabolism)
• Drug Resistance, Neoplasm (genetics)
• Female
• Humans
• Ovarian Neoplasms (drug therapy)
• Poly(ADP-ribose) Polymerase Inhibitors (pharmacology, therapeutic use)