KRas Induces a Src/PEAK1/ErbB2 Kinase Amplification Loop That Drives Metastatic Growth and Therapy Resistance in Pancreatic Cancer
KRas Induces a Src/PEAK1/ErbB2 Kinase Amplification Loop That Drives Metastatic Growth and Therapy Resistance in Pancreatic Cancer
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DOI：
10.1158/0008-5472.can-11-3552
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发表时间：
2012-05-15
期刊：
影响因子：
11.2
通讯作者：
Klemke, Richard L.
中科院分区：
文献类型：
--
作者：
Kelber, Jonathan A.;Reno, Theresa;Klemke, Richard L.
胰腺导管腺癌（PDAC）的5年生存率很低，迫切需要早期生物标志物和有效的治疗策略来治疗。在这里，我们报告说，新的酪氨酸激酶PEAK 1在人类恶性肿瘤，包括人类PDAC和胰腺上皮内瘤（PanIN）上调。致癌性KRas诱导Src、PEAK 1和ErbB 2之间的PEAK 1依赖性激酶扩增环，以驱动PDAC肿瘤在体内的生长和转移。令人惊讶的是，ErbB 2表达的阻断增加了Src依赖性PEAK 1表达、PEAK 1依赖性Src活化和体内肿瘤生长，表明了PDAC患者对治疗干预的观察到的抗性的机制。重要的是，PEAK 1失活使PDAC细胞对曲妥珠单抗和吉西他滨治疗敏感。因此，我们的研究结果表明，PEAK 1是PDAC中的一种新的生物标志物、关键信号传导中心和新的治疗靶点。Cancer Res; 72（10）; 2554-64. (C)2012年AACR。
Early biomarkers and effective therapeutic strategies are desperately needed to treat pancreatic ductal adenocarcinoma (PDAC), which has a dismal 5-year patient survival rate. Here, we report that the novel tyrosine kinase PEAK1 is upregulated in human malignancies, including human PDACs and pancreatic intraepithelial neoplasia (PanIN). Oncogenic KRas induced a PEAK1-dependent kinase amplification loop between Src, PEAK1, and ErbB2 to drive PDAC tumor growth and metastasis in vivo. Surprisingly, blockade of ErbB2 expression increased Src-dependent PEAK1 expression, PEAK1-dependent Src activation, and tumor growth in vivo, suggesting a mechanism for the observed resistance of patients with PDACs to therapeutic intervention. Importantly, PEAK1 inactivation sensitized PDAC cells to trastuzumab and gemcitabine therapy. Our findings, therefore, suggest that PEAK1 is a novel biomarker, critical signaling hub, and new therapeutic target in PDACs. Cancer Res; 72(10); 2554-64. (C) 2012 AACR.