Poly(ADP-ribose) polymerase inhibitors in triple-negative breast cancer

Abstract

Poly(ADP-ribose) polymerases (PARPs) are involved in many aspects of the cellular response to various forms of damage. PARP-1 and PARP-2, the most abundant PARPs, are central to the response to specific types of DNA damage, especially single-strand breaks. Inhibition of PARP activity may sensitize the cell to exogenous agents such as chemotherapy and radiation. In circumstances where rescue pathways are deficient, particularly the homologous recombination (HR)-directed DNA repair pathway, inhibition of PARP may result in "synthetic lethality." BRCA mutation-associated breast cancers are a paradigm of HR-directed repair deficient tumors. Early clinical trials have demonstrated significant activity of single-agent PARP inhibitors in BRCAdeficient breast and ovarian cancer. Because of phenotypic similarities between some "triplenegative" breast cancers (TNBC) and the most prevalent type of breast cancer seen in BRCA1 mutation carriers, some have hypothesized that TNBC might also be specifically sensitive to PARP inhibition. The activity of single-agent PARP inhibitors in TNBC has not been reported. One trial did suggest significant enhancement of the activity of platinum-based combination chemotherapy, without incremental toxicity. These studies indicate that PARP inhibition is an exciting new approach to the treatment of breast cancers in women with underlying BRCA mutations and possibly in sporadic cancers with defects in HR-directed repair. Future studies will be necessary to determine whether the effectiveness of PARP inhibitors in nonhereditary cancer requires an underlying HR defect or whether these agents may improve the activity of conventional chemotherapy by other means. In addition, studies will be required to determine whether PARP inhibitors may induce synthetic lethality in tumors with defects in pathways other than the BRCA-dependent DNA repair pathway. If either or both of these prove to be the case, then PARP inhibition may benefit a wide spectrum of cancer patients. Keywordspoly(ADP-ribose) polymerase (PARP); BRCA1; BRCA2; "basal-like," DNA repair; base excision repair; homologous recombination-directed repair; synthetic lethality Poly(ADP-ribose) polymerases (PARPs) are a family of enzymes that share the ability to transfer adenosine phosphate (ADP)-ribose subunits from nicotinamide dinucleotide + onto PARPs are involved in a number of process, including inflammation and the cellular response to response to various insults, such as ischemia or oxidative stress. 6 For instance, PARP activation, with consequent depletion of nicotinamide dinucleotide + , may be an important determinant of cell death after ischemia. 7 However, it is the role of PARPs in DNA damage repair that is of greatest interest to oncology therapeutics. INVOLVEMENT OF PARPS IN DNA DAMAGE REPAIRThe maintenance of genomic integrity is a critical cellular function. Endogenous and exogenous insults result in various forms of DNA damage on a regular basis, and a number of pathways have evolved to address these lesions. 8,9 PA...