The Evolution of PARP Inhibitors in Prostate Cancer
Abstract
Poly(adenosine diphosphate [ADP]‑ribose) polymerase (PARP) inhibitors induce cell death in cancers by exploiting synthetic lethality, in which the combination of two defective cellular processes are lethal; however, either defect alone is not lethal. PARP inhibitors impair the base excision repair pathway, which functions to repair single strand DNA breaks. Thus PARP inhibitors result in unrepaired single strand breaks, which are converted to double strand breaks during cellular replication. In a normally functioning cell, these double strand breaks are of little consequence, as the homologous recombination repair (HRR) pathway functions to repair these breaks efficiently and accurately. However, in the cellular background of defective HRR, classically through loss of BRCA1 or BRCA2 (BRCA1/2) protein function, the accumulation of these double strand breaks results in severe genomic stress and ultimately cell death.
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