Dasatinib synergizes with both cytotoxic and signal transduction inhibitors in heterogeneous breast cancer cell lines--lessons for design of combination targeted therapy.
Molecularly targeted therapies have emerged as the leading theme in cancer therapeutics. Multi-cytotoxic drug regimens have been highly successful, yet many studies in targeted therapeutics have centered on a single agent. We investigated whether the Src/Abl kinase inhibitor dasatinib displays synergy with other agents in molecularly heterogeneous breast cancer cell lines. MCF-7, SKBR-3, and MDA-MB-231 display different signaling and gene signatures profiles due to expression of the estrogen receptor, ErbB2, or neither. Cell proliferation was measured following treatment with dasatinib±cytotoxic (paclitaxel, ixabepilone) or molecularly targeted agents (tamoxifen, rapamycin, sorafenib, pan PI3K inhibitor LY294002, and MEK/ERK inhibitor U0126). Dose-responses for single or combination drugs were calculated and analyzed by the Chou-Talalay method. The drugs with the greatest level of synergy with dasatinib were rapamycin, ixabepilone, and sorafenib, for the MDA-MB-231, MCF-7, and SK-BR-3 cell lines respectively. However, dasatinib synergized with both cytotoxic and molecularly targeted agents in all three molecularly heterogeneous breast cancer cell lines. These results suggest that effectiveness of rationally designed therapies may not entirely rest on precise identification of gene signatures or molecular profiling. Since a systems analysis that reveals emergent properties cannot be easily performed for each cancer case, multi-drug regimens in the near future will still involve empirical design.
Departments of Pediatrics and Cell & Molecular Biology, Children's Memorial Hospital, Northwestern University, Feinberg School of Medicine, IL, USA.
Brian J
BJ
Park
Zakary L
ZL
Whichard
Seth J
SJ
Corey
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001557:Benzenesulfonates / Q000008:administration & dosage / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy*; D002070:Butadienes / Q000008:administration & dosage / Q000494:pharmacology; D045744:Cell Line, Tumor; D002867:Chromones / Q000008:administration & dosage / Q000494:pharmacology; D000069439:Dasatinib; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D034261:Epothilones / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D006801:Humans; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology; D009536:Niacinamide / Q000031:analogs & derivatives; D009570:Nitriles / Q000008:administration & dosage / Q000494:pharmacology; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology; D010671:Phenylurea Compounds; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology; D000077157:Sorafenib; D013629:Tamoxifen / Q000008:administration & dosage / Q000494:pharmacology; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*
D001557:Benzenesulfonates; D002070:Butadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D034261:Epothilones; D009025:Morpholines; D009570:Nitriles; D010671:Phenylurea Compounds; D011725:Pyridines; D011743:Pyrimidines; D013844:Thiazoles; C113580:U 0126; D013629:Tamoxifen; D009536:Niacinamide; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D000077157:Sorafenib; C430592:ixabepilone; D017239:Paclitaxel; D000069439:Dasatinib; D020123:Sirolimus