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
Menée in vitro et in vivo, cette étude évalue la combinaison d'un inhibiteur de PARP, appelé ABT-888, et de sels de platine pour le traitement d'un cancer du sein présentant une mutation BRCA1 ou BRCA2
Individuals with an inherited BRCA1 or BRCA2 mutation have an elevated risk of developing breast cancer (BC). 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(ADP)ribose polymerase (PARP) inhibitors (PARPi) have been demonstrated for BRCA-associated cancers. However, there is 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 survival of treated Brca-proficient and -deficient mouse embryonic stem cells (mESC). In addition, drug-induced growth inhibition of a BRCA1 and a BRCA2 null cell line were compared to their isogenic BRCA-complemented lines. Whereas 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, apoptosis and greater PARP activity in Brca/BRCA-deficient cells, and 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 BRCA patients.
http://mct.aacrjournals.org/content/early/2012/07/07/1535-7163.MCT-11-0597.abstract