Editorial: Inhibiting PARP as a Strategic Target in Cancer

When Christina Annunziata and I embarked on guest editing an e-journal about poly(ADP-ribose) polymerase (PARP) inhibitors for cancer therapy, our goal was to capture how one of the most promising, rationally developed therapies had become increasingly complex in clinical use. We recruited an outstanding group of researchers to help in this effort. We organize their contributions into two broad categories, those with a more basic science approach and those with a more clinical approach, although these are not without overlap. Beginning with the more mechanistic contributions, " The Elephant and the Blind Men: Making Sense of PARP Inhibitors in Homologous Recombination Deficient Tumor Cells " by De Lorenzo et al. provides an excellent review of the main models proposed to explain the synthetic lethality seen with PARP inhibition and deficiency in homologous recombination. Limitations of the models are highlighted, along with the potential impact that our knowledge gaps might have on clinical application of PARP inhibition. This article provides the groundwork for critical consideration of the other papers in this compilation. In " Strategic Combination of DNA Damaging Agent and PARP Inhibitor Results in Enhanced Cytotoxicity, " Horton and Wilson describe using a mouse embryonic fibroblast cell culture model to better understand how PARP-1 inhibition impacts cell killing in combination with various chemo-therapeutic agents. They report that the chemistry of the DNA repair intermediate that is formed is critical to PARP inhibitor-induced sensitization. This level of detail complements that presented by Steffen et al. who contributed " Structural Implications for Selective Targeting of PARPs. " The authors delve into the question of whether PARP inhibition should be targeted to all PARPs through binding to conserved regions or more selective in targeting specific PARPs. The answer has the potential to impact both PARP inhibitor effectiveness and toxicity. Poly(ADP-ribose) polymerase enzymes are most widely recognized for their roles in single-strand DNA repair, especially when complementing the double-strand repair that is dependent on BRCA proteins. It is important to realize, however, that the PARP enzymes have other functions in the cell. In " Beyond DNA Repair: Additional Functions of PARP-1 in Cancer, " Weaver and Yang broaden our focus on PARP inhibition from the typically discussed DNA damage response to other processes, such as inflammation, angiogenesis, cellular metabolism, and cell death, that are critical to cancer biology. This information helps interpret some side effects of the PARP inhibitors in the clinic and hints …