RESISTANCE TO PARP INHIBITORS

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  As with all anti-cancer therapies, eventual resistance to PARP inhibitors occurs and a search for mechanisms of resistance is ongoing. One confirmed resistance mechanism is restored BRCA1/2 function through the acquisition of reversion mutations.  Edwards (84), Sakai (85) and Swisher (86) identified reversion mutations as an explanation for PARP inhibitor resistance.  Subsequent work by Norquist and colleagues evaluating germline BRCA1/2 ovarian tumors after acquiring platinum resistance suggests that reversion mutations may happen relatively frequently and may be the cause of this phenotype (87).  These results also explain why Fong and colleagues observed that platinum sensitive patients experience greater clinical efficacy from PARP inhibitors compared to platinum resistant patients (64).

Another potential mechanism of resistance is tumor loss of 53BP1.  In general, homozygous BRCA1 mice knockouts are not viable and those homozygous for mutations which produce BRCA protein but with significantly reduced function (BRCA^∆11/∆11) have premature aging and high malignancy rates.  Cao and colleagues demonstrated that mice embryos homozygous for BRCA^∆11/∆11 mutation could be rescued from premature aging and malignancy by knocking out 53BP1 function (23).  Bunting and colleagues subsequently showed that elimination of 53BP1 activity in BRCA1 deficient cells restores RAD51 foci. As BRCA1 prevents 53BP1 from interfering with MRN-mediated end-resection in HR-proficient cells, it is likely that by removing 53BP1 function in BRCA1 deficient cells MRN-mediated end-resection is no longer prevented, facilitating HR repair (22).  In addition, Bouwman and colleagues demonstrated that loss of 53BP1 could restore the viability of embryonic stem cells following acute loss of BRCA1 function (88).  These observations suggest that 53BP1 loss in tumor cells may represent a mechanism of resistance to PARP inhibitors by restoring end-resection activity in BRCA1-mutated cancers.  One remaining issue is what compensation mechanisms exist to overcome the role of BRCA1 in other aspects of HR repair following 53BP1 loss; this question is under current study.