The Role of MET Receptor Tyrosine Kinase in Non-Small Cell Lung Cancer and Clinical Development of Targeted Anti-MET Agents
The Role of MET Receptor Tyrosine Kinase in Non-Small Cell Lung Cancer and Clinical Development of Targeted Anti-MET Agents
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DOI：
10.1634/theoncologist.2012-0262
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发表时间：
2013-02-01
期刊：
影响因子：
5.8
通讯作者：
Sandler, Alan B.
中科院分区：
文献类型：
--
作者：
Robinson, Kyle W.;Sandler, Alan B.
对非小细胞肺癌（NSCLC）病理生理学和演变的更好理解已经确定了许多分子靶点，并刺激了新型靶向治疗剂的开发。MET受体酪氨酸激酶及其配体肝细胞生长因子（HGF）与包括NSCLC在内的多种人类癌症的肿瘤细胞增殖、迁移、侵袭和血管生成有关。据报道，约5%-22%的肺肿瘤对表皮生长因子受体（EGFR）的小分子抑制剂具有获得性耐药性，MET扩增。对EGFR抑制剂的耐药性可能是通过磷酸肌醇3-激酶/AKT通路的下游激活介导的。用MET抑制剂加EGFR抑制剂同时治疗耐药肿瘤可以消除细胞生长、增殖和存活的下游效应物的激活，从而克服对EGFR抑制剂的获得性耐药性。靶向HGF-MET通路的多种药物（包括靶向HGF或MET受体的单克隆抗体和MET酪氨酸激酶的小分子抑制剂）的开发和临床前试验证实了该通路在NSCLC中的关键作用。几种药物目前处于治疗NSCLC的III期临床开发阶段。本文综述了MET在NSCLC病理生理学和EGFR抑制剂获得性耐药中的作用，并提供了MET抑制剂治疗NSCLC临床开发的最新进展。肿瘤学家2013;18：115-122
A better understanding of the pathophysiology and evolution of non-small cell lung cancer (NSCLC) has identified a number of molecular targets and spurred development of novel targeted therapeutic agents. The MET receptor tyrosine kinase and its ligand hepatocyte growth factor (HGF) are implicated in tumor cell proliferation, migration, invasion, and angiogenesis in a broad spectrum of human cancers, including NSCLC. Amplification of MET has been reported in approximately 5%-22% of lung tumors with acquired resistance to small-molecule inhibitors of the epidermal growth factor receptor (EGFR). Resistance to EGFR inhibitors is likely mediated through downstream activation of the phosphoinositide 3-kinase/AKT pathway. Simultaneous treatment of resistant tumors with a MET inhibitor plus an EGFR inhibitor can abrogate activation of downstream effectors of cell growth, proliferation, and survival, thereby overcoming acquired resistance to EGFR inhibitors. Development and preclinical testing of multiple agents targeting the HGF-MET pathway, including monoclonal antibodies targeting HGF or the MET receptor and small-molecule inhibitors of the MET tyrosine kinase, have confirmed the crucial role of this pathway in NSCLC. Several agents are now in phase III clinical development for the treatment of NSCLC. This review summarizes the role of MET in the pathophysiology of NSCLC and in acquired resistance to EGFR inhibitors and provides an update on progress in the clinical development of inhibitors of MET for treatment of NSCLC. The Oncologist 2013;18:115-122