The emerging potential of poly(ADP-ribose) polymerase inhibitors in the treatment of breast cancer.
The nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) represents an important novel target in cancer therapy. It is essential for the repair of single-strand DNA breaks via the base excision repair pathway. Inhibitors of PARP-1 were first developed as chemosensitizers. However, preclinical data suggest that PARP inhibitors can act as single agents to selectively kill cancers with BRCA (breast cancer associated) 1 or 2 mutations and cancers harbouring defects in other DNA repair proteins. Why PARP inhibitors are synthetically lethal to certain tumours and the specific role this class of drugs may play in the treatment of breast cancer is reviewed. Phase I clinical trial results confirm that PARP inhibitors have single agent activity in cancers with BRCA 1/2 mutations. Phase II data also suggest a benefit in combination with chemotherapy in triple-negative breast cancers without an increase in normal tissue toxicity. There are currently eight PARP inhibitors in clinical trial development worldwide. Data from early clinical trials suggest a role in the treatment of BRCA-related and triple-negative breast cancer. A wider role for this class of drug in breast cancer is proposed; however, as little is known about the long-term effects of these drugs, we should proceed with caution and await results of the ongoing clinical trials.