Advances in the use of PARP inhibitor therapy for breast cancer

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Abstract

Poly-ADP-ribose polymerase 1 (PARP-1) and PARP-2 are DNA damage sensors that are most active during S-phase of the cell cycle and that have wider-reaching roles in DNA repair than originally described. BRCA1 and BRCA2 (Breast Cancer) proteins are involved in homologous recombination repair (HRR), which requires a homologous chromosome or sister chromatid as a template to faithfully repair DNA double-strand breaks. The small-molecule NAD+ mimetics, olaparib, niraparib, rucaparib, veliparib, and talazoparib, inhibit the catalytic activity of PARP-1 and PARP-2 and are currently being studied in later-stage clinical trials. PARP inhibitor clinical trials have predominantly focused on patients with breast and ovarian cancer with deleterious germline BRCA1 and BRCA2 mutations (gBRCA1/2+) but are now expanding to include cancers with known, suspected, or morelikely- than-not defects in homologous recombination repair. In ovarian cancer, this group also includes women whose cancers are responsive to platinum therapy. Olaparib was FDA-approved in January 2018 for the treatment of gBRCA1/2+ metastatic breast cancers. gBRCA1+ predisposes women to develop triple-negative breast cancers, while women with gBRCA2+ tend to develop hormone-receptor-positive, human epidermal growth factor receptor 2 negative breast cancers. Although PARP inhibitor monotherapy strategies seem most effective in cancers with homologous recombination repair defects, combination strategies may allow expansion into a wider range of cancers. By interfering with DNA repair, PARP inhibitors essentially sensitize cells to DNA-damaging chemotherapies and radiation therapy. Certainly, one could also consider expanding the utility of PARP inhibitors beyond gBRCA1/2+ cancers by causing DNA damage with cytotoxic agents in the presence of a DNA repair inhibitor. Unfortunately, in numerous phase I clinical trials utilizing a combination of cytotoxic chemotherapy at standard doses with dose-escalation of PARP inhibitors, there has generally been failure to reach monotherapy dosages of PARP inhibitors due to myelosuppressive toxicities. Strategies utilizing angiogenesis inhibitors and immune checkpoint inhibitors are generally not hindered by additive toxicities, though the utility of combining PARP inhibitors with treatments that have not been particularly effective in breast cancers somewhat tempers enthusiasm. Finally, there are combination strategies that may serve to mitigate resistance to PARP inhibitors, namely, upregulation of the intracellular PhosphoInositide-3-kinase, AK thymoma (protein kinase B), mechanistic target of rapamycin (PI3K–AKT–mTOR) pathway, or perhaps are more simply meant to interfere with a cell growth pathway heavily implicated in breast cancers while administering relatively well-tolerated PARP inhibitor therapy.

Keywords: BRCA1, BRCA2, breast cancer, niraparib, olaparib, PARP inhibitor, rucaparib, talazoparib, veliparib.

Citation: McCann KE, Hurvitz SA. Advances in the use of PARP inhibitor therapy for breast cancer. Drugs in Context 2018; 7: 212540. DOI: 10.7573/dic.212540

Disclosure and potential conflicts of interest: Dr McCann has nothing to disclose. Dr Hurvitz reports: grants and nonfinancial support from Ambryx, Amgen, Bayer, BI Pharma, Biomarin, Cascadian, Daiichi Sankyo, Dignitana, Genentech, GSK, Lilly, Macrogenics, Medivation, Merrimack, Novartis, OBI Pharma, Pfizer, Pieris, PUMA, Roche, and Seattle Genetics; other from Lilly, Novartis, and OBI Pharma, during the conduct of the study. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors are available for download at https://www.drugsincontext.com/wp-content/uploads/2018/07/dic.212540-COI.pdf

Funding declaration: There was no funding for this manuscript.

Copyright: Copyright © 2018 McCann KE, Hurvitz SA. Published by Drugs in Context under Creative Commons License Deed CC BY NC ND 4.0 which allows anyone to copy, distribute, and transmit the article provided it is properly attributed in the manner specified below. No commercial use without permission.

Correct attribution: Copyright © 2018 McCann KE, Hurvitz SA. https://doi.org/10.7573/dic.212540. Published by Drugs in Context under Creative Commons License Deed CC BY NC ND 4.0.

Article URL: https://www.drugsincontext.com/advances-in-the-use-of-parp-inhibitor-therapy-for-breast-cancer

Correspondence: Kelly E. McCann, UCLA Dept of Medicine, Division of Hematology/Oncology, 2336 Santa Monica Suite 304, Santa Monica, CA 90404, USA. kmccann@mednet.ucla.edu

Provenance: invited; externally peer reviewed.

Submitted: 28 May 2018; Peer review comments to author: 4 July 2018; Revised manuscript received: 5 July 2018; Accepted: 9 July 2018; Publication date: 8 August 2018.

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