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 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.
Department of Cancer Biology, Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope, Duarte, California 91010, USA.
Caroline C
CC
Clark
Jeffrey N
JN
Weitzel
Timothy R
TR
O'Connor
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001562:Benzimidazoles / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016466:CHO Cells; D016190:Carboplatin / Q000008:administration & dosage; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism; D004336:Drug Antagonism; D004357:Drug Synergism; D004720:Endonucleases / Q000378:metabolism; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051135:Rad51 Recombinase / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D001562:Benzimidazoles; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; D016190:Carboplatin; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; C071447:ERCC1 protein, human; D004720:Endonucleases