Four individually druggable MET hotspots mediate HGF-driven tumor progression
Four individually druggable MET hotspots mediate HGF-driven tumor progression
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DOI：
10.1172/jci72316
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发表时间：
2014-07-01
影响因子：
15.9
通讯作者：
Michieli, Paolo
中科院分区：
文献类型：
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作者：
Basilico, Cristina;Hultberg, Anna;Michieli, Paolo
HGF激活MET在肿瘤进展中起关键作用。使用最近开发的产生类人免疫球蛋白的美洲驼平台，我们选择了68种不同的抗体，这些抗体与HGF竞争结合MET。HGF竞争性抗体识别位于不同MET结构域中的4个不同热点。我们鉴定了1个热点，其与SEMA结构域β-螺旋桨的叶片2-3上的已知HGF β链结合位点一致。我们确定了第二和第三个热点位于SEMA结构域的叶片5和IPT结构域2-3内，这两个结构域都被认为与HGF α链结合。第四个热点的表征揭示了跨PSI-IPT 1结构域的先前不与HGF结合相关的区域。这些热点的单独或组合靶向在多个基于细胞的生化和生物测定中有效地中断HGF/MET信号传导。针对SEMA叶片2-3和PSI-IPT 1区域的所选抗体在多形性胶质母细胞瘤模型中抑制脑侵袭并延长存活，在三阴性乳腺癌模型中预防新辅助治疗后的转移性疾病，并在KRAS突变转移性结肠直肠癌模型中抑制癌细胞向肝脏的传播。这些结果确定了负责HGF介导的肿瘤进展的MET的多个区域，揭示了HGF-MET相互作用的复杂性，并为靶向癌症中的MET活性提供了选择性分子工具。
Activation of MET by HGF plays a key role in tumor progression. Using a recently developed llama platform that generates human-like immunoglobulins, we selected 68 different antibodies that compete with HGF for binding to MET. HGF-competing antibodies recognized 4 distinct hotspots localized in different MET domains. We identified 1 hotspot that coincides with the known HGF beta chain binding site on blades 2-3 of the SEMA domain beta-propeller. We determined that a second and a third hotspot lie within blade 5 of the SEMA domain and IPT domains 2-3, both of which are thought to bind to HGF alpha chain. Characterization of the fourth hotspot revealed a region across the PSI-IPT 1 domains not previously associated with HGF binding. Individual or combined targeting of these hotspots effectively interrupted HGF/MET signaling in multiple cell-based biochemical and biological assays. Selected antibodies directed against SEMA blades 2-3 and the PSI-IPT 1 region inhibited brain invasion and prolonged survival in a glioblastoma multiform e model, prevented metastatic disease following neoadjuvant therapy in a triple-negative mammary carcinoma model, and suppressed cancer cell dissemination to the liver in a KRAS-mutant metastatic colorectal cancer model. These results identify multiple regions of MET responsible for HGF-mediated tumor progression, unraveling the complexity of HGF-MET interaction, and provide selective molecular tools for targeting MET activity in cancer.