Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3.
Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3.
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DOI：
10.1038/nature05474
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发表时间：
2007-01-25
期刊：
影响因子：
64.8
通讯作者：
Moasser, Mark M.
中科院分区：
文献类型：
--
作者：
Sergina, Natalia V.;Rausch, Megan;Wang, Donghui;Blair, Jimmy;Hann, Byron;Shokat, Kevan M.;Moasser, Mark M.
致癌性酪氨酸激酶已被证明是开发高效抗癌药物的有前途的靶点。然而，HER家族酪氨酸激酶抑制剂（TKI）对HER 2驱动的癌症仅显示有限的活性，尽管在体内有效抑制EGFR和HER 2。其原因尚不清楚。反式信号传导是该多成员家族的关键特征，并且至关重要的PI 3 K/Akt途径主要通过激酶失活的HER 3的转磷酸化驱动。我们报告了HER 3和PI 3 K/Akt信号转导逃避了目前HER家族TKI在体外和体内肿瘤中的抑制。这是由于HER 3磷酸化-去磷酸化平衡的补偿性偏移，其由驱动磷酸化反应的膜HER 3表达增加和阻碍去磷酸化反应的HER 3磷酸酶活性降低驱动。这些补偿性变化是由Akt介导的负反馈信号驱动的。尽管HER 3不是TKI的直接靶点，但HER 3底物耐药性破坏了其疗效，迄今尚未被检测到。通过siRNA敲低消除HER 3抗性的实验性消除恢复了对其他细胞抑制性HER TKI的强效促凋亡作用，再次肯定了HER 2驱动肿瘤的癌基因成瘾性质和该癌蛋白靶点的治疗前景。然而，由于HER 3信号传导对HER 2激酶的不完全抑制有缓冲作用，因此需要更有效的TKI或联合策略来有效沉默致癌HER 2信号传导。指导HER TKI的生物标志物应该是HER 3的转磷酸化。
Oncogenic tyrosine kinases have proven to be promising targets for the development of highly effective anticancer drugs. However HER family tyrosine kinase inhibitors (TKIs) show only limited activity against HER2-driven cancers despite effective inhibition of EGFR and HER2 in vivo . The reasons for this are unclear. Signaling in trans is a key feature of this multimember family and the critically important PI3K/Akt pathway is driven predominantly through transphosphorylation of the kinase-inactive HER3. We report that HER3 and consequently PI3K/Akt signaling evade inhibition by current HER family TKIs in vitro and in tumors in vivo. This is due to a compensatory shift in HER3 phosphorylation-dephosphorylation equilibrium driven by increased membrane HER3 expression driving the phosphorylation reaction and reduced HER3 phosphatase activity impeding the dephosphorylation reaction. These compensatory changes are driven by Akt mediated negative feedback signaling. Although HER3 is not a direct target of TKIs, HER3 substrate resistance undermines their efficacy and has thus far gone undetected. The experimental abbrogation of HER3 resistance by siRNA knockdown restores potent pro-apoptotic effects to otherwise cytostatic HER TKIs, re-affirming the oncogene-addicted nature of HER2-driven tumors and the therapeutic promise of this oncoprotein target. However, since HER3 signaling is buffered against an incomplete inhibition of HER2 kinase, much more potent TKIs or combination strategies are required to effectively silence oncogenic HER2 signaling. The biologic marker to guide HER TKIs should be the transphosphorylation of HER3.
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影响因子：
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