Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
Oncogene. 2011 Aug 18;30(33):3625-35. doi: 10.1038/onc.2011.84. Epub 2011 Mar 21.
The c-Met receptor is a potential therapeutic target for non-small cell lung cancer (NSCLC). Signaling interactions between c-Met and the mutant epidermal growth factor receptor (EGFR) have been studied extensively, but signaling intermediates and biological consequences of lateral signaling to c-Met in EGFR wild-type tumors are minimally understood. Our observations indicate that delayed c-Met activation in NSCLC cell lines is initiated by wild-type EGFR, the receptor most often found in NSCLC tumors. EGFR ligands induce accumulation of activated c-Met, which begins at 8 h and continues for 48 h. This effect is accompanied by an increase in c-Met expression and phosphorylation of critical c-Met tyrosine residues without activation of mitogen-activated protein kinase (MAPK) or Akt. Gene transcription is required for delayed c-Met activation; however, phosphorylation of c-Met by EGFR occurs without production of hepatocyte growth factor (HGF) or another secreted factor, supporting a ligand-independent mechanism. Lateral signaling is blocked by two selective c-Met tyrosine kinase inhibitors (TKIs), PF2341066 and SU11274, or with gefitinib, an EGFR TKI, suggesting kinase activity of both receptors is required for this effect. Prolonged c-Src phosphorylation is observed, and c-Src pathway is essential for EGFR to c-Met communication. Pretreatment with pan-Src family kinase inhibitors, PP2 and dasatinib, abolishes delayed c-Met phosphorylation. A c-Src dominant-negative construct reduces EGF-induced c-Met phosphorylation compared with control, further confirming a c-Src requirement. Inhibition of c-Met with PF2341066 and siRNA decreases EGF-induced phenotypes of invasion by ~86% and motility by ~81%, suggesting that a novel form of c-Met activation is utilized by EGFR to maximize these biological effects. Combined targeting of c-Met and EGFR leads to increased xenograft antitumor activity, demonstrating that inhibition of downstream and lateral signaling from the EGFR-c-Src-c-Met axis might be effective in treatment of NSCLC.
c-Met 受体是治疗非小细胞肺癌（NSCLC）的潜在靶点。c-Met 与突变表皮生长因子受体（EGFR）之间的信号相互作用已经得到了广泛研究，但 EGFR 野生型肿瘤中侧向信号向 c-Met 的信号转导中间物和生物学后果知之甚少。我们的观察表明，NSCLC 细胞系中 c-Met 的延迟激活是由 EGFR 启动的，EGFR 是 NSCLC 肿瘤中最常见的受体。EGFR 配体诱导激活的 c-Met 积累，这一效应始于 8 小时，并持续 48 小时。这一效应伴随着 c-Met 表达的增加和关键 c-Met 酪氨酸残基的磷酸化，而丝裂原活化蛋白激酶（MAPK）或 Akt 没有被激活。基因转录是延迟 c-Met 激活所必需的；然而，EGFR 对 c-Met 的磷酸化发生在没有产生肝细胞生长因子（HGF）或另一种分泌因子的情况下，支持一种非配体依赖的机制。两种选择性 c-Met 酪氨酸激酶抑制剂（TKIs）PF2341066 和 SU11274 或 EGFR TKI 吉非替尼阻断侧向信号，表明这一效应需要两个受体的激酶活性。观察到持续的 c-Src 磷酸化，并且 c-Src 途径对于 EGFR 到 c-Met 的通讯是必需的。用 pan-Src 家族激酶抑制剂 PP2 和 dasatinib 预处理可消除延迟的 c-Met 磷酸化。与对照相比，c-Src 显性失活构建体减少了 EGF 诱导的 c-Met 磷酸化，进一步证实了 c-Src 的需求。用 PF2341066 和 siRNA 抑制 c-Met 可使 EGF 诱导的侵袭表型减少约 86%，运动性减少约 81%，表明 EGFR 利用一种新形式的 c-Met 激活来最大限度地发挥这些生物学效应。c-Met 和 EGFR 的联合靶向导致异种移植物抗肿瘤活性增加，表明抑制 EGFR-c-Src-c-Met 轴的下游和侧向信号可能是治疗 NSCLC 的有效方法。
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