c-Src activation mediates erlotinib resistance in head and neck cancer by stimulating c-Met.
c-Src activation mediates erlotinib resistance in head and neck cancer by stimulating c-Met.
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DOI：
10.1158/1078-0432.ccr-12-1555
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发表时间：
2013-01-15
期刊：
影响因子：
--
通讯作者：
Grandis JR
中科院分区：
文献类型：
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作者：
Stabile LP;He G;Lui VW;Thomas S;Henry C;Gubish CT;Joyce S;Quesnelle KM;Siegfried JM;Grandis JR
使用酪氨酸激酶抑制剂 (TKI) 厄洛替尼抑制表皮生长因子受体 (EGFR) 的策略与头颈鳞状细胞癌 (HNSCC) 的临床疗效有限相关。替代激酶的共激活可能导致厄洛替尼耐药。我们生成了表达显性活性 c-Src (DA-Src) 的 HNSCC 细胞，以确定 c-Src 激活对厄洛替尼反应的贡献。与载体转染的对照细胞（VC）相比，DA-Src 的表达在体外和体内赋予厄洛替尼耐药性。 Phospho-Met 被 DA-Src 强烈上调，并且 DA-Src 细胞不产生肝细胞生长因子 (HGF)。在体外，c-Met 的敲低增强了 DA-Src 细胞对厄洛替尼的敏感性，将 c-Met 或 c-Src 抑制剂与厄洛替尼联合使用也是如此。抑制 EGFR 会导致 DA-Src 细胞中磷酸 Met 的最小减少，而通过抑制 c-Src 可以实现完全磷酸 Met 抑制。 c-Met 抑制剂在体内使 DA-Src 肿瘤对厄洛替尼显着敏感，导致 Ki67 标记减少并增加细胞凋亡。在亲代细胞中，内源性 c-Src 的敲低增强了对厄洛替尼的敏感性，而用 HGF 直接诱导磷酸化 Met 的治疗会导致厄洛替尼耐药。 HNSCC 细胞系中内源性磷酸-c-Src 的水平也与厄洛替尼耐药性显着相关。在 c-Src 激活的 HNSCC 中，c-Met 的配体独立激活特别导致厄洛替尼耐药，而不是西妥昔单抗耐药，其中 c-Met 激活更依赖于 c-Src，而不是 EGFR，从而提供了替代的生存途径。在厄洛替尼中添加 c-Met 或 c-Src 抑制剂可能会提高 c-Src 激活患者中 EGFR 抑制的疗效。
Strategies to inhibit the epidermal growth factor receptor (EGFR) using the tyrosine kinase inhibitor (TKI) erlotinib have been associated with limited clinical efficacy in head and neck squamous cell carcinoma (HNSCC). Co-activation of alternative kinases may contribute to erlotinib resistance. We generated HNSCC cells expressing dominant-active c-Src (DA-Src) to determine the contribution of c-Src activation to erlotinib response. Expression of DA-Src conferred resistance to erlotinib in vitro and in vivo compared with vector-transfected control cells (VC). Phospho-Met was strongly upregulated by DA-Src, and DA-Src cells did not produce hepatocyte growth factor (HGF). Knockdown of c-Met enhanced sensitivity to erlotinib in DA-Src cells in vitro, as did combining a c-Met or c-Src inhibitor with erlotinib. Inhibiting EGFR resulted in minimal reduction of phospho-Met in DA-Src cells, whereas complete phospho-Met inhibition was achieved by inhibiting c-Src. A c-Met inhibitor significantly sensitized DA-Src tumors to erlotinib in vivo, resulting in reduced Ki67 labeling and increased apoptosis. In parental cells, knockdown of endogenous c-Src enhanced sensitivity to erlotinib, while treatment with HGF to directly induce phospho-Met resulted in erlotinib resistance. The level of endogenous phospho-c-Src in HNSCC cell lines was also significantly correlated with erlotinib resistance. Ligand-independent activation of c-Met contributes specifically to erlotinib resistance, not cetuximab resistance, in HNSCC with activated c-Src, where c-Met activation is more dependent on c-Src than on EGFR, providing an alternate survival pathway. Addition of a c-Met or c-Src inhibitor to erlotinib may increase efficacy of EGFR inhibition in patients with activated c-Src.