Disclosure of Erlotinib as a Multikinase Inhibitor in Pancreatic Ductal Adenocarcinoma
Disclosure of Erlotinib as a Multikinase Inhibitor in Pancreatic Ductal Adenocarcinoma
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DOI：
10.1593/neo.111016
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发表时间：
2011-11-01
期刊：
影响因子：
4.8
通讯作者：
Schneider, Guenter
中科院分区：
文献类型：
--
作者：
Conradt, Laura;Godl, Klaus;Schneider, Guenter
一项安慰剂对照的3期试验表明，表皮生长因子受体（EGFR）抑制剂厄洛替尼与吉西他滨联合治疗胰腺导管腺癌（PDAC）皮肤毒性患者亚组尤其有效。然而，EGFR表达不能预测缓解，目前还缺少表征厄洛替尼缓解PDAC组的标志物。在这项工作中，我们在一组人和鼠PDAC细胞系中观察到高埃罗替尼IC（50）值。使用EGFR小干扰RNA，我们检测到厄洛替尼的反应受EGFR的影响很小。为了找到新的EGFR靶点，我们使用了无偏倚的化学蛋白质组学方法进行靶点鉴定和质量控制的靶点亲和力测定，并结合基于细胞培养物中氨基酸稳定同位素标记的定量质谱法。与吉非替尼相反，我们通过定量蛋白质组学观察到厄洛替尼在PDAC细胞中的广泛靶向分布。6种蛋白激酶与厄洛替尼的结合亲和力（K（d）= 0.09-0.358 μ M）与EGFR（K（d）0.434 μ M）相似或更高。我们提供的证据表明，厄洛替尼的新靶点之一ARG在一定程度上促进了PDAC细胞系中厄洛替尼的反应。我们的数据表明，厄洛替尼是一种多激酶抑制剂，在PDAC中可以独立于EGFR发挥作用。这些发现可能有助于监测未来的厄洛替尼临床试验。
A placebo-controlled phase 3 trial demonstrated that the epidermal growth factor receptor (EGFR) inhibitor erlotinib in combination with gemcitabine was especially efficient in a pancreatic ductal adenocarcinoma (PDAC) subgroup of patients developing skin toxicity. However, EGFR expression was not predictive for response, and markers to characterize an erlotinib-responding PDAC group are currently missing. In this work, we observed high erlotinib IC(50) values in a panel of human and murine PDAC cell lines. Using EGFR small interfering RNA, we detected that the erlotinib response was marginally influenced by EGFR. To find novel EGFR targets, we used an unbiased chemical proteomics approach for target identification and quality-controlled target affinity determination combined with quantitative mass spectrometry based on stable isotope labeling by amino acids in cell culture. In contrast to gefitinib, we observed a broad target profile of erlotinib in PDAC cells by quantitative proteomics. Six protein kinases bind to erlotinib with similar or higher affinity (K(d) = 0.09-0.358 mu M) than the EGFR (K(d) 0.434 mu M). We provide evidence that one of the novel erlotinib targets, ARG, contributes in part to the erlotinib response in a PDAC cell line. Our data show that erlotinib is a multikinase inhibitor, which can act independent of EGFR in PDAC. These findings may help to monitor future erlotinib trials in the clinic.