Preclinical Development Enhancement of Synthetic Lethality via Combinations of ABT-888, a PARP Inhibitor, and Carboplatin In Vitro and In Vivo Using BRCA1 and BRCA2 Isogenic Models

Individuals with an inherited BRCA1 or BRCA2mutation have an elevated risk of developing breast cancer. The resulting tumors typically lack homologous recombination repair as do a subset of sporadic tumors with acquired BRCA deficiency. Clinical responses to monotherapy with platinum drugs or poly PARP inhibitors (PARPi)havebeenshown forBRCA-associatedcancers.However, thereare limiteddataoncombination therapy with PARPi and platinumdrugs, themechanism of action of this combination, and the role of BRCA1 or BRCA2 in chemosensitivity. We compared the efficacy of ABT-888 (a PARPi) with that of cisplatin or carboplatin (platinum drugs) alone or in combinations by examining the survival of treated Brca-proficient and -deficient mouse embryonic stemcells. In addition, drug-induced growth inhibition of a BRCA1 and aBRCA2null cell line were comparedwith their isogenic BRCA-complemented lines. Although eachmonotherapy killed or inhibited proliferation of Brca/BRCA-deficient cells, an enhanced effect was observed after treatment with ABT-888 in combinationwith carboplatin.Moreover, theABT-888/carboplatin combination delayed tumor growth inBrca2 xenografts. The drugs caused DNA damage and apoptosis. Along with greater PARP activity in Brca/BRCAdeficient cells, these effects correlated with increased chemosensitivity. Our data suggest that ABT-888 and carboplatin combination treatment will be more successful than monotherapy in addressing many BRCAassociated cancers. A randomized phase II trial has recently been initiated to test this hypothesis to assist in the discovery of more effective therapies for patients with BRCA. Mol Cancer Ther; 11(9); 1948–58. 2012 AACR.