Combination of farnesyltransferase and Akt inhibitors is synergistic in breast cancer cells and causes significant breast tumor regression in ErbB2 transgenic mice.
Combination of farnesyltransferase and Akt inhibitors is synergistic in breast cancer cells and causes significant breast tumor regression in ErbB2 transgenic mice.
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DOI：
10.1158/1078-0432.ccr-10-2544
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发表时间：
2011-05-01
期刊：
影响因子：
--
通讯作者：
Sebti SM
中科院分区：
文献类型：
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作者：
Balasis ME;Forinash KD;Chen YA;Fulp WJ;Coppola D;Hamilton AD;Cheng JQ;Sebti SM
Akt激活抑制剂曲西立滨和法尼基转移酶抑制剂替吡法尼在临床试验中作为单一药物使用时具有适度至很小的活性。在该手稿中，临床前数据表明，该组合在培养细胞和体内均比单药更有效。组合指数数据分析表明，该组合在抑制乳腺癌细胞的锚定依赖性生长方面具有高度协同作用。这种协同相互作用也与Akt（MK-2206）和法尼基转移酶（FTI-2153）的结构无关的抑制剂观察到。在几种癌细胞系中观察到曲西立滨/替吡法尼的协同效应，所述癌细胞系包括来自乳腺癌、白血病、多发性骨髓瘤和肺肿瘤的具有不同遗传改变如K-Ras、B-Raf、PI 3 K、p53和pRb突变、PTEN、pRB和Ink 4a缺失以及ErbB受体过表达的那些。此外，该组合在抑制乳腺癌细胞中的锚定非依赖性生长和诱导细胞凋亡方面具有协同作用。该组合在抑制Akt/mTOR/S6激酶途径方面也更有效。在ErbB 2驱动的乳腺肿瘤转基因小鼠模型中，曲西立滨和替吡法尼的组合而非单一药剂治疗诱导显著的乳腺肿瘤消退。我们的研究结果值得进一步调查法尼基转移酶和Akt抑制剂的组合。
The Akt activation inhibitor triciribine and the farnesyltransferase inhibitor tipifarnib have modest to little activity in clinical trials when used as single agents. In this manuscript pre-clinical data demonstrate that the combination is more effective than single agents both in cultured cells and in vivo. Combination index data analysis demonstrates that this combination is highly synergistic at inhibiting anchorage-dependent growth of breast cancer cells. This synergistic interaction is also observed with structurally unrelated inhibitors of Akt (MK-2206) and farnesyltransferase (FTI-2153). The triciribine/tipifarnib synergistic effects are seen with several cancer cell lines including those from breast, leukemia, multiple myeloma and lung tumors with different genetic alterations such as K-Ras, B-Raf, PI3K, p53 and pRb mutations, PTEN, pRB and Ink4a deletions and ErbB receptor overexpression. Furthermore, the combination is synergistic at inhibiting anchorage-independent growth and at inducing apoptosis in breast cancer cells. The combination is also more effective at inhibiting the Akt/mTOR/S6 kinase pathway. In an ErbB2-driven breast tumor transgenic mouse model the combination, but not single agent, treatment with triciribine and tipifarnib induces significant breast tumor regression. Our findings warrant further investigation of the combination of farnesyltransferase and Akt inhibitors.