PDF file, 131K, SUPPLEMENTARY FIGURE S3. Clonogenic cell survival of isogenic VC8 (Brca2-deficient) and VC8+Brca2 (Brca2-complemented) CHO cells after treatment with ABT-888, carboplatin, cisplatin alone or ABT-888 combined with a platinum drug. VC8 and VC8+Brca2 cells were treated for 6 days with the indicated drugs and concentrations. (A) ABT-888, (B) carboplatin, and (C) ABT-888/carboplatin. Data represent the average of triplicate measurements. Error bars, mean + SEM. (D) Interaction effects of ABT-888 with carboplatin treatment in VC8 CHO cell line.
ARTICLE ABSTRACT
Individuals with an inherited BRCA1 or BRCA2 mutation 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) have been shown for BRCA-associated cancers. However, there are limited data on combination therapy with PARPi and platinum drugs, the mechanism 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 stem cells. In addition, drug-induced growth inhibition of a BRCA1 and a BRCA2 null cell line were compared with their isogenic BRCA-complemented lines. Although each monotherapy killed or inhibited proliferation of Brca/BRCA-deficient cells, an enhanced effect was observed after treatment with ABT-888 in combination with carboplatin. Moreover, the ABT-888/carboplatin combination delayed tumor growth in Brca2 xenografts. The drugs caused DNA damage and apoptosis. Along with greater PARP activity in Brca/BRCA-deficient 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 BRCA-associated 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.
