Targeting the c-Met signaling pathway in cancer
Targeting the c-Met signaling pathway in cancer
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DOI：
10.1158/1078-0432.ccr-06-0818
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发表时间：
2006-06-15
影响因子：
11.5
通讯作者：
Bottaro, Donald P.
中科院分区：
文献类型：
--
作者：
Peruzzi, Benedetta;Bottaro, Donald P.
在与称为c-Met的细胞表面受体酪氨酸激酶（TK）结合时，肝细胞生长因子（HGF）刺激广泛范围的细胞靶标中的有丝分裂、运动发生和形态发生，所述细胞靶标包括上皮细胞和内皮细胞、造血细胞、神经元、黑素细胞和肝细胞。这些多效性作用在发育、体内平衡和组织再生过程中至关重要。HGF信号传导还有助于几种人类癌症中的肿瘤发生和肿瘤进展，并促进与肿瘤转移密切相关的侵袭性细胞侵袭。我们目前对c-Met致癌信号传导的理解支持至少三种途径选择性抗癌药物开发：配体/受体相互作用的拮抗作用，TK催化活性的抑制作用和细胞内受体/效应物相互作用的阻断作用。使用这三种策略已经开发出了有效的和有选择性的临床前候选药物，目前正在三个领域中的两个领域进行人体临床试验。
On binding to the cell surface receptor tyrosine kinase (TK) known as c-Met, hepatocyte growth factor (HGF) stimulates mitogenesis, motogenesis, and morphogenesis in a wide range of cellular targets including, epithelial and endothelial cells, hematopoietic cells, neurons, melanocytes, and hepatocytes. These pleiotropic actions are fundamentally important during development, homeostasis, and tissue regeneration. HGF signaling also contributes to oncogenesis and tumor progression in several human cancers and promotes aggressive cellular invasiveness that is strongly linked to tumor metastasis. Our present understanding of c-Met oncogenic signaling supports at least three avenues of pathway selective anticancer drug development: antagonism of ligand/receptor interaction, inhibition of TK catalytic activity, and blockade of intracellular receptor/effector interactions. Potent and selective preclinical drug candidates have been developed using all three strategies, and human clinical trials in two of the three areas are now under way.