Paracrine Receptor Activation by Microenvironment Triggers Bypass Survival Signals and ALK Inhibitor Resistance in EML4-ALK Lung Cancer Cells
Paracrine Receptor Activation by Microenvironment Triggers Bypass Survival Signals and ALK Inhibitor Resistance in EML4-ALK Lung Cancer Cells
复制标题
DOI：
10.1158/1078-0432.ccr-11-2972
复制
发表时间：
2012-07-01
影响因子：
11.5
通讯作者：
Yano, Seiji
中科院分区：
文献类型：
--
作者：
Yamada, Tadaaki;Takeuchi, Shinji;Yano, Seiji
目的：癌细胞微环境，包括宿主细胞，可以严重影响癌细胞的行为，包括药物敏感性。虽然克唑替尼是一种ALK和Met的双重酪氨酸激酶抑制剂（TKI），对EML 4-ALK肺癌细胞显示出显著的作用，但这些细胞可通过多种机制获得对克唑替尼的耐药，包括ALK扩增和看门突变。我们确定微环境因素是否触发EML 4-ALK肺癌细胞中ALK抑制剂的耐药性。我们检测了内皮细胞和成纤维细胞产生的配体以及细胞本身对EML 4-ALK肺癌细胞系对克唑替尼和TAE 684（一种对ALK扩增和看门突变细胞具有活性的选择性ALK抑制剂）的敏感性的影响，结果：EML 4-ALK肺癌细胞对ALK抑制剂高度敏感。EGF受体（EGFR）配体，如EGF、TGF-α和HB-EGF，通过Erk 1/2和Akt转导旁路生存信号，激活EGFR并触发对克唑替尼和TAE 684的耐药性。肝细胞生长因子（HGF）激活Met/Gab 1并触发对TAE 684的耐药性，但不激活抑制Met的克唑替尼。分别产生EGFR配体和HGF的内皮细胞和成纤维细胞分别降低了EML 4-ALK肺癌细胞对克唑替尼和TAE 684的敏感性。EGFR-TKI使这些细胞对克唑替尼和Met-TKI对TAE 684重新敏感，即使在EGFR配体和HGF存在的情况下也是如此，分别。结论：来自微环境的配体激活的旁分泌受体可能引发EML 4-ALK肺癌细胞对ALK抑制剂的耐药性，这表明来自微环境的受体配体可能是ALK抑制剂治疗期间的额外靶点。临床癌症研究; 18（13）; 3592-602。（C）2012年AACR。
Purpose: Cancer cell microenvironments, including host cells, can critically affect cancer cell behaviors, including drug sensitivity. Although crizotinib, a dual tyrosine kinase inhibitor (TKI) of ALK and Met, shows dramatic effect against EML4-ALK lung cancer cells, these cells can acquire resistance to crizotinib by several mechanisms, including ALK amplification and gatekeeper mutation. We determined whether microenvironmental factors trigger ALK inhibitor resistance in EML4-ALK lung cancer cells.Experimental Design: We tested the effects of ligands produced by endothelial cells and fibroblasts, and the cells themselves, on the susceptibility of EML4-ALK lung cancer cell lines to crizotinib and TAE684, a selective ALK inhibitor active against cells with ALK amplification and gatekeeper mutations, both in vitro and in vivo.Results: EML4-ALK lung cancer cells were highly sensitive to ALK inhibitors. EGF receptor (EGFR) ligands, such as EGF, TGF-alpha, and HB-EGF, activated EGFR and triggered resistance to crizotinib and TAE684 by transducing bypass survival signaling through Erk1/2 and Akt. Hepatocyte growth factor (HGF) activated Met/Gab1 and triggered resistance to TAE684, but not crizotinib, which inhibits Met. Endothelial cells and fibroblasts, which produce the EGFR ligands and HGF, respectively, decreased the sensitivity of EML4-ALK lung cancer cells to crizotinib and TAE684, respectively. EGFR-TKIs resensitized these cells to crizotinib and Met-TKI to TAE684 even in the presence of EGFR ligands and HGF, respectively.Conclusions: Paracrine receptor activation by ligands from the microenvironment may trigger resistance to ALK inhibitors in EML4-ALK lung cancer cells, suggesting that receptor ligands from microenvironmentmay be additional targets during treatment with ALK inhibitors. Clin Cancer Res; 18(13); 3592-602. (C)2012 AACR.