Department of Clinical and Experimental Medicine, Second University of Naples, Italy.
Curr Pharm Des. 2012;18(37):6155-68. doi: 10.2174/138161212803582478.
Lung cancer, of which non-small-cell lung cancer (NSCLC) is the most common form, remains the leading cause of cancer-related mortality worldwide, with many patients presenting with advanced disease at initial diagnosis. In advanced NSCLC patients whose tumors harbor activating epidermal growth factor receptor (EGFR) mutations, the use of EGFR tyrosine kinase inhibitors (TKIs) as first-line treatment has provided an unusually large progression-free-survival (PFS) benefit, a significantly high response rate (RR) and decreased toxicity when compared with cytotoxic chemotherapy in several phase III randomized trials; however, resistance invariably occurs. There are multiple mechanisms defined by which tumor cells may become independent of EGFR such as the well-characterized example of mesenchymal-epithelial transition factor (MET) amplification. Upon initial diagnosis of NSCLC, MET gene amplification is uncommon; however, acquired MET amplification has been noted in up to 20% of EGFR-mutated tumors that have been pretreated with an EGFR TKI. In tumors containing MET gene amplification, stimulation of the tumor occurs via the co-receptor HER-3 resulting in activation of the phosphatidylinositol-3-kinase (PI3K) signaling pathway, thereby circumventing the effects of an EGFR TKI. Recently, the targeting of the MET pathway has been attempted with small molecules and with monoclonal antibodies. This review will explain the MET signaling pathway and biology in cancer and the recent clinical development and advances of MET/HGF targeting agents in the treatment of advanced NSCLC.
肺癌，其中非小细胞肺癌（NSCLC）最为常见，仍然是全球癌症相关死亡的主要原因，许多患者在初始诊断时就已处于晚期疾病。在肿瘤携带激活表皮生长因子受体（EGFR）突变的晚期 NSCLC 患者中，EGFR 酪氨酸激酶抑制剂（TKI）作为一线治疗已提供了异常大的无进展生存期（PFS）获益，与细胞毒性化疗相比，具有显著更高的缓解率（RR）和降低的毒性；然而，耐药性不可避免地会发生。已经确定了肿瘤细胞可能变得不依赖于 EGFR 的多种机制，例如众所周知的间质上皮转化因子（MET）扩增。在 NSCLC 的初始诊断中，MET 基因扩增并不常见；然而，在接受 EGFR TKI 预处理的 EGFR 突变肿瘤中，已注意到获得性 MET 扩增高达 20%。在含有 MET 基因扩增的肿瘤中，通过共受体 HER-3 刺激肿瘤发生，导致磷酸肌醇-3-激酶（PI3K）信号通路的激活，从而规避 EGFR TKI 的作用。最近，已经尝试使用小分子和单克隆抗体来靶向 MET 途径。这篇综述将解释 MET 信号通路和癌症生物学，以及最近 MET/HGF 靶向药物在治疗晚期 NSCLC 方面的临床开发和进展。
