7 - The future of PARP inhibitors in the treatment of cancer

Summary

Introduction

A better understanding of the molecular biology of cancer is leading to the identification of distinct cancer sub-types, new anti-cancer targets and more individualised treatment approaches. Since the discovery of the first polyadenosine diphosphate-ribose polymerase (PARP) enzyme over 40 years ago, the abundant nuclear enzyme has emerged as an important novel target in cancer therapy. PARP-1 is activated by DNA damage and plays a crucial role in the repair of DNA single-strand breaks (SSBs) via the base excision repair (BER) pathway. Inhibitors of PARP-1 have been shown to enhance the cytotoxic effects of ionising radiation and DNA-damaging chemotherapeutic agents. In addition, pre-clinical data and early-phase clinical trial results suggest that PARP inhibitors can be used as single agents to selectively kill cancers defective in DNA repair pathways, specifically cancers with mutations in the tumour suppressor genes BRCA1 and BRCA2. Germline mutations in either BRCA1 or BRCA2 result in defective homologous recombination (HR) DNA double-strand break (DSB) repair and are associated with a high lifetime risk of breast and ovarian cancer. Synthetic lethality is defined as the lethal effect of inactivating two enzymes or pathways when inactivation of either enzyme or pathway alone is non-lethal. In cells with BRCA1/2 mutations, which are defective in HR DNA repair, PARP inhibitors can induce synthetic lethality by inactivating the BER pathway. This leads to the accumulation of DNA SSBs that during replication are converted to DSBs, which are normally repaired by the HR pathway.