Targeting Hsp90 prevents escape of breast cancer cells from tyrosine kinase inhibition.
Targeting Hsp90 prevents escape of breast cancer cells from tyrosine kinase inhibition.
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DOI：
10.4161/cc.7.18.6701
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发表时间：
2008-09-15
期刊：
影响因子：
--
通讯作者：
Neckers L
中科院分区：
文献类型：
--
作者：
Pashtan I;Tsutsumi S;Wang S;Xu W;Neckers L
最近的研究已经确定了对酪氨酸激酶抑制（TKI）的耐药性的发展是有效治疗的一个重要障碍。最近发现的一种耐药机制涉及“癌基因转换”，或通过一个或多个冗余上游激活因子重新激活信号通路。在乳腺癌模型中，尽管ErbB抑制作用得以维持，但随着时间的推移，gefitinib等ErbB TKIs已被证明失去了调节ErbB驱动的信号通路的能力。虽然ErB抑制不完全是导致这一现象的原因，但我们的研究结果表明，癌基因转换也可以重新激活乳腺癌细胞中的下游信号通路，即使ErB抑制完全。我们发现ErbB TKI诱导的Src激活介导SKBR3细胞的下游信号反弹，并且我们发现Src和ErbB抑制剂联合使用比单独使用TKI更有效和持久。最后，Hsp90抑制剂17-AAG通过同时和持久地抑制多种信号激活因子，包括ErbB和Src激酶，不允许癌基因转换，导致比单个TKIs对乳腺癌细胞下游信号通路的更持久和更强的抑制。这些数据支持Hsp90抑制剂在乳腺癌中的持续临床评价。
Recent studies have identified development of resistance to tyrosine kinase inhibition (TKI) as a significant roadblock to effective treatment. One mechanism of resistance recently appreciated involves ‘oncogene switching’, or the re-activation of signaling pathways by one or more redundant upstream activators. In breast cancer models, ErbB TKIs such as gefitinib have been shown to lose the ability to modulate ErbB-driven signaling pathways over time, even though ErbB inhibition is maintained. Although incomplete ErB inhibition has been proposed to underlie this phenomenon, our findings suggest that oncogene switching can also re-activate downstream signaling pathways in breast cancer cells, even when ErbB inhibition is complete. We find that ErbB TKI-induced Src activation mediates downstream signaling rebound in SKBR3 cells, and we show that combination of Src and ErbB inhibitors is more effective and longlasting than is either TKI alone. Finally, the Hsp90 inhibitor 17-AAG, by simultaneously and durably inhibiting multiple signaling activators including ErbB and Src kinases, does not permit oncogene switching and results in a more prolonged and robust inhibition of downstream signaling pathways in breast cancer cells than do individual TKIs. These data support the continued clinical evaluation of Hsp90 inhibitors in breast cancer.
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