Response to Crizotinib in a Patient With Lung Adenocarcinoma Harboring a MET Splice Site Mutation.
Response to Crizotinib in a Patient With Lung Adenocarcinoma Harboring a MET Splice Site Mutation.
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DOI：
10.1016/j.cllc.2015.01.009
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发表时间：
2015-09
影响因子：
3.6
通讯作者：
Barbie DA
中科院分区：
文献类型：
--
作者：
Jenkins RW;Oxnard GR;Elkin S;Sullivan EK;Carter JL;Barbie DA
MET（c-Met;间充质-上皮转化因子）是一种受体酪氨酸激酶，其在1984年首次在化学转化的骨肉瘤细胞系中被表征为原癌基因。1 MET基因位于染色体7 q21 -31，编码一个细胞表面受体酪氨酸激酶，由一个50 kDa的α链和一个140 kDa的跨膜β链组成，通过二硫键连接。c-Met的天然配体是肝细胞生长因子（HGF），也称为散射因子。2 HGF与c-Met受体结合后，c-Met受体发生二聚化和磷酸化，进而促进下游效应蛋白的募集，导致MAPK、PI 3 K/Akt、STAT和NF-κB通路等多个信号通路的激活。3 HGF/MET信号传导的生理作用包括胚胎发生、发育和伤口愈合。3，4，5 c-Met受体酪氨酸激酶的异常激活促进肺腺癌亚群的致癌性。多种机制可导致组成性c-Met信号传导，包括MET基因扩增、蛋白过表达、激活点突变和诱导其配体HGF。3，6，7克唑替尼是一种多靶点酪氨酸激酶抑制剂，已被美国食品药品监督管理局批准用于治疗携带ALK融合的肺腺癌，并对ROS 1重排的肺腺癌具有活性（但尚未被FDA批准用于该适应症），8，9，10最近还发现其在具有高水平MET扩增的肿瘤中具有临床活性。11这些发现促使临床开发更具选择性的c-Met抑制剂，用于在这一特定患者人群中进行评估。
MET (c-Met; mesenchymal–epithelial transition factor) is a receptor tyrosine kinase that was first characterized as a proto-oncogene in 1984 in a chemically transformed osteosarcoma cell line. 1 Located on chromosome 7q21-31, the MET gene encodes a cell surface receptor tyrosine kinase composed of a 50 kDa α chain and a 140 kDa transmembrane β chain linked by a disulfide bond. The natural ligand for c-Met is hepatocyte growth factor (HGF), also known as scatter factor. 2 After binding of HGF, the c-Met receptor undergoes dimerization and phosphorylation, which in turn promotes recruitment of downstream effector proteins, leading to activation of multiple signaling cascades, including the MAPK, PI3K/Akt, STAT and NF-κB pathways. 3 Physiologic roles for HGF/MET signaling include embryogenesis, development, and wound healing. 3, 4, 5Aberrant activation of the c-Met receptor tyrosine kinase promotes oncogenicity in a subset of lung adenocarcinomas. A variety of mechanisms can result in constitutive c-Met signaling, including MET gene amplification, protein overexpression, activating point mutations, and induction of its ligand HGF. 3, 6, 7 Crizotinib, a multitargeted tyrosine kinase inhibitor that is approved by the US Food and Drug Administration for the therapy of lung adenocarcinomas harboring ALK fusions and has activity in ROS1-rearranged lung adenocarcinoma (but is not yet FDA-approved for this indication), 8, 9, 10 was also recently found to be clinically active in tumors with high level MET amplification. 11 These findings have prompted the clinical development of more selective c-Met inhibitors for evaluation in this particular patient population.