The Hepatocyte Growth Factor Receptor: Structure, Function and Pharmacological Targeting in Cancer.
The Hepatocyte Growth Factor Receptor: Structure, Function and Pharmacological Targeting in Cancer.
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DOI：
10.2174/157436211795659955
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发表时间：
2011
影响因子：
--
通讯作者：
Bottaro DP
中科院分区：
文献类型：
--
作者：
Cecchi F;Rabe DC;Bottaro DP
在正常情况下，肝细胞生长因子(HGF)诱导的细胞表面受体Met酪氨酸激酶(TK)的激活受到旁分泌配体传递、靶细胞表面配体激活以及配体激活受体内化和降解的严格调控。尽管有这些控制，HGF/Met信号有助于几种癌症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。HGF/Met通路激活在人类恶性肿瘤中的流行推动了抗癌药物开发计划的快速增长。途径抑制剂大致可分为生物制剂和低分子合成的TK抑制剂；在这些药物中，后者的数量现在超过了所有其他类型的抑制剂。本文就Met的结构和功能、HGF/Met途径拮抗剂的基本性质、临床前和临床研究进展以及最新的临床试验结果作一综述。HGF/Met靶向拮抗剂有效用于癌症治疗面临的主要挑战包括最佳的患者选择、诊断和药效生物标记物的开发，以及最佳治疗组合的识别和测试。关于HGF/Met致癌信号的丰富的基本信息、分析试剂和模型系统在应对这些挑战和迅速实现更有效的疾病控制方面将继续发挥无价的作用。
Under normal conditions, hepatocyte growth factor (HGF)-induced activation of its cell surface receptor, the Met tyrosine kinase (TK), is tightly regulated by paracrine ligand delivery, ligand activation at the target cell surface, and ligand activated receptor internalization and degradation. Despite these controls, HGF/Met signaling contributes to oncogenesis and tumor progression in several cancers and promotes aggressive cellular invasiveness that is strongly linked to tumor metastasis. The prevalence of HGF/Met pathway activation in human malignancies has driven rapid growth in cancer drug development programs. Pathway inhibitors can be divided broadly into biologicals and low molecular weight synthetic TK inhibitors; of these, the latter now outnumber all other inhibitor types. We review here Met structure and function, the basic properties of HGF/Met pathway antagonists now in preclinical and clinical development, as well as the latest clinical trial results. The main challenges facing the effective use of HGF/Met-targeted antagonists for cancer treatment include optimal patient selection, diagnostic and pharmacodynamic biomarker development, and the identification and testing of optimal therapy combinations. The wealth of basic information, analytical reagents and model systems available concerning HGF/Met oncogenic signaling will continue to be invaluable in meeting these challenges and moving expeditiously toward more effective disease control.