Poly-ADP-ribose polymerases (PARPs) as a therapeutic target in the treatment of selected cancers

ABSTRACT

Introduction: The implementation of poly-ADP-ribose polymerase (PARP) inhibitors for therapy has created potential treatments for a wide spectrum of malignancies involving DNA damage repair gene abnormalities. PARPs are a group of enzymes that are responsible for detecting and repairing DNA damage and therefore play a key role in maintaining cell function and integrity. PARP inhibitors are drugs that target DNA repair deficiencies. Inhibiting PARP activity in cancer cells causes cell death.

Areas covered: This review summarizes the role of PARP inhibitors in the treatment of cancer. We performed a systematic literature search in February 2019 in the electronic databases PubMed and EMBASE. Our search terms were the following: PARP, PARP inhibitors, PARPi, Poly ADP ribose polymerase, cancer treatment. We discuss PARP inhibitors currently being investigated in cancer clinical trials, their safety profiles, clinical resistance, combined therapeutic approaches and future challenges.

Expert Opinion: The future could bring novel PARP inhibitors with greater DNA trapping potential, better safety profiles and improved combined therapies involving hormonal, chemo-, radio- or immunotherapies. Progress may afford wider indications for PARP inhibitors in the treatment of cancer and the utilization for cancer prevention in high-risk mutation carriers. Research efforts should focus on identifying novel drugs that target DNA repair deficiencies.

KEYWORDS:

• PARP enzymes
• PARP inhibitors
• DNA damage response
• BRCA mutations
• BRCAness
• ovarian cancer
• breast cancer
• prostate cancer

Article Highlights

• PARP inhibitors hold potential as treatments for a wide spectrum of malignancies involving somatic or germinal DNA damage repair gene abnormalities.

• The concept of the clinical use of PARP inhibitors is based on a phenomenon called ‘synthetic lethality’, and the most potent molecules also have DNA trapping potential. The main targets of these drugs are cancer cells with DDR repair gene defects (BRCA1, BRCA2 and others).

• The chemical structures of PARP inhibitors are based on a few scaffolds and characteristic moieties. Novel particles are being designated and tested.

• Few PARP inhibitors are currently approved for the treatment of ovarian and breast cancers, but many others are being tested in clinical trials with either wider indications or applications for other cancers (notably prostate cancer).

• PARP inhibitors treatment is generally considered safe, but there might be some adverse effects that could limit treatment feasibility.

• There is a promising opportunity to further augment treatment effects by identifying suitable patients (using advanced genetic testing) and combining PARP inhibitors with other drugs, for example, immune checkpoint inhibitors.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded.