Dasatinib synergizes with both cytotoxic and signal transduction inhibitors in heterogeneous breast cancer cell lines--lessons for design of combination targeted therapy.
Dasatinib synergizes with both cytotoxic and signal transduction inhibitors in heterogeneous breast cancer cell lines--lessons for design of combination targeted therapy.
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DOI：
10.1016/j.canlet.2012.01.039
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发表时间：
2012-07-01
期刊：
影响因子：
9.7
通讯作者：
Corey, Seth J.
中科院分区：
文献类型：
--
作者：
Park, Brian J.;Whichard, Zakary L.;Corey, Seth J.
分子靶向治疗已成为癌症治疗的主导主题。多细胞毒性药物治疗方案非常成功，但许多靶向治疗研究都集中在单一药物上。我们研究了 Src/Abl 激酶抑制剂达沙替尼是否与其他药物在分子异质性乳腺癌细胞系中表现出协同作用。由于雌激素受体、ErbB2 的表达或两者都不表达，MCF-7、SKBR-3 和 MDA-MB-231 显示出不同的信号传导和基因特征谱。用达沙替尼±细胞毒性药物（紫杉醇、伊沙匹隆）或分子靶向药物（他莫昔芬、雷帕霉素、索拉非尼、泛 PI3K 抑制剂 LY294002 和 MEK/ERK 抑制剂 U0126）治疗后测量细胞增殖。通过 Chou-Talalay 方法计算和分析单一或组合药物的剂量反应。与达沙替尼具有最大协同作用的药物是雷帕霉素、伊沙匹隆和索拉非尼，分别针对 MDA-MB-231、MCF-7 和 SK-BR-3 细胞系。然而，达沙替尼在所有三种分子异质性乳腺癌细胞系中与细胞毒性药物和分子靶向药物具有协同作用。这些结果表明，合理设计的疗法的有效性可能并不完全取决于基因特征或分子谱的精确识别。由于无法轻松地对每个癌症病例进行揭示新兴特性的系统分析，因此在不久的将来，多种药物治疗方案仍将涉及经验设计。
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.
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DOI：
10.1093/jnci/53.3.661
发表时间：
1974-01-01
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
CAILLEAU, R;YOUNG, R;REEVES, WJ
通讯作者：
REEVES, WJ
DOI：
10.1158/1541-7786.mcr-09-0528
发表时间：
2010-07
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Lapuk A;Marr H;Jakkula L;Pedro H;Bhattacharya S;Purdom E;Hu Z;Simpson K;Pachter L;Durinck S;Wang N;Parvin B;Fontenay G;Speed T;Garbe J;Stampfer M;Bayandorian H;Dorton S;Clark TA;Schweitzer A;Wyrobek A;Feiler H;Spellman P;Conboy J;Gray JW
通讯作者：
Gray JW
影响因子：
11.5
作者：
Carlos Montero, Juan;Seoane, Samuel;Pandiella, Atanasio
通讯作者：
Pandiella, Atanasio
影响因子：
78.5
作者：
Chabner, BA;Roberts, TG
通讯作者：
Roberts, TG
影响因子：
64.5
作者：
Bollenbach T;Quan S;Chait R;Kishony R
通讯作者：
Kishony R