Therapeutic potential of PARP inhibitors for metastatic breast cancer

Abstract

Increasing understanding of the cellular aberrations inherent to cancer cells has allowed the development of therapies to target biological pathways, an important step towards individualization of breast cancer therapy. The clinical development of poly(ADP-ribose) polymerase (PARP) inhibitors, with their novel and selective mechanism of action, are an example of this strategy. PARP plays a key role in DNA repair mechanisms, particularly the base excision repair pathway. Initially developed as inhibitors able to enhance the cytotoxicity of radiation and certain DNA-damaging agents, they have more recently been shown to have single-agent activity in certain tumors. Inhibition of PARP in a DNA repair-defective tumor can lead to gross genomic instability and cell death by exploiting the paradigm of synthetic lethality. Several studies have evaluated the role of PARP inhibitors for treatment of breast cancer, particularly in the context of BRCA-mutated and triple-negative breast cancers. In addition, inhibition of PARPs repair functions for chemotherapy-induced DNA lesions has been shown to potentiate the effect of some chemotherapy regimens. This article discusses the current understanding of PARP inhibition as a treatment for metastatic breast cancer, evidence from clinical trials and addresses its future implications.

Keywords::

• basal-like
• breast cancer
• BRCA1
• BRCA2
• DNA repair
• homologous repair
• PARP inhibitors
• triple-negative breast cance

Financial & competing interests disclosure

Alan Ashworth and Andrew Tutt may benefit financially from the development of PARP inhibitors through patents held jointly with AstraZeneca through the Institute of Cancer Research ‘rewards to inventors’ scheme. Andrew Tutt has acted as an unpaid or paid consultant and/or received honoraria for Pfizer, Eisai, sanofi-aventis, AstraZeneca and Clovis Inc. and has received research funding from sanofi-aventis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.