PARP Inhibitors in Cancer Therapy: Magic Bullets but Moving Targets.

摘要

The pharmacological inhibitors ofudpoly(ADP-ribose) polymerase-1 (PARP-ud1) have reached the first milestone towardudtheir inclusion in the arsenal of anti-canceruddrugs by showing consistent benefitsudin clinical trials against BRCA-mutantudcancers that are deficient in the homologousudrecombination repair (HRR) ofudDNA double strand breaks (DSB) (1,ud2). PARP inhibitors (PARPi) also potentiateudtherapeutic efficacy of ionizingudradiation and some chemotherapeuticudagents (1). These effects of PARPiudwere initially linked to inhibition of theudrole of PARP-1 in base excision repairud(BER) of DNA damaged by endogenousudor exogenous agents, resulting inudaccumulation of single strand breaksud(SSB), which upon conversion to toxicudDSB lesions would kill cancer cells deficientudin DSB repair (1, 3, 4). However,udPARPi lethality in HRR-deficient cancersudcan also be explained by other mechanismsudnot involving a direct effect ofudPARPi on BER [reviewed in Ref. (5,ud6)]. In addition, therapeutic benefitsudof PARPi with agents such as carboplatinudin HRR-proficient and -deficientudtumors [reviewed in Ref. (1, 7)], simplyudcannot be explained by BER inhibitoryudeffect of PARPi. Therefore, PARPi areudlike magic bullets that can kill cancerudcells under different circumstances,udbut to comprehend their global scopeudand limitations, here we discuss the fulludrange of their targets and the possibleudimpact of broad specificity of currentudPARPi during prolonged therapy of cancerudpatients.