Poly(ADP-ribose) polymerase inhibitors as promising cancer therapeutics

Abstract

The year of 2005 was a watershed in the history of poly(ADP-ribose) polymerase (PARP) inhibitors due to the important findings of selective killing in BRCA-deficient cancers by PARP inhibition. The findings made PARP inhibition one of the most promising new therapeutic approaches to cancers, especially to those with specific defects. With AZD2281 and BSI-201 entering phase III clinical trials, the final application of PARP inhibitors in clinic would come true soon. This current paper will review the major advances in targeting PARP for cancer therapy and discuss the existing questions, the answers to which may influence the future of PARP inhibitors as cancer therapeutics.

Figure 1

A schematic presentation of the rationale of targeting PARPs for cancer therapy. Inhibition of PARPs impairs the repair for DNA single-strand breaks (SSB), which then accumulate in the cell. When colliding the progressing replication forks, those SSB are converted to DNA double-strand breaks (DSB) that are generally repaired through the homologous recombination (HR) pathway. Defects in the HR pathway such as the functional mutations of BRCA1 or BRCA2 disable the repair for those DSB and confer lethality to them. This is so called as “synthetic lethality”. On the other hand, if the HR pathway functions normally under PARP inhibition, additional introduction of exogenous SSB as induced by irradiation or certain DNA damaging drugs may produce excessive DSB that overwhelm the HR repair. Consequently, those excessive, unrepaired DSB kill the cell.