Discovery and Therapeutic Exploitation of Mechanisms of Resistance to MET Inhibitors in Glioblastoma.
Discovery and Therapeutic Exploitation of Mechanisms of Resistance to MET Inhibitors in Glioblastoma.
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DOI：
10.1158/1078-0432.ccr-18-0926
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发表时间：
2019-01-15
期刊：
影响因子：
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通讯作者：
Abounader R
中科院分区：
文献类型：
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作者：
Cruickshanks N;Zhang Y;Hine S;Gibert M;Yuan F;Oxford M;Grello C;Pahuski M;Dube C;Guessous F;Wang B;Deveau C;Saoud K;Gallagher I;Wulfkuhle J;Schiff D;Phan S;Petricoin E;Abounader R
胶质母细胞瘤（GBM）是最常见和最致命的原发性恶性脑肿瘤。 GBM 中受体酪氨酸激酶 MET 经常上调或过度激活。尽管已经开发出临床适用的 MET 抑制剂，但对单一模式抗 MET 药物的耐药性经常发生，导致这些药物无效。我们的目的是确定 GBM 中 MET 抑制剂耐药的机制，并利用获得的信息开发新的治疗方法来克服耐药性。我们研究了两种临床适用的 MET 抑制剂：克唑替尼（一种 ATP 竞争性小分子 MET 抑制剂）和 Onartuzumab（一种与 MET 受体胞外域结合的单价单克隆抗体）。我们开发了新的 MET 抑制剂耐药细胞系和动物模型，并利用反相蛋白阵列 (RPPA) 和功能测定来揭示 MET 抑制剂耐药 GBM 的补偿途径。我们鉴定了 MET 抑制剂耐药 GBM 中发生改变的关键蛋白，包括 mTOR、FGFR1、EGFR、STAT3 和 COX-2。与单独使用任一药物相比，同时抑制 MET 和其中一种上调蛋白会导致耐药细胞中细胞死亡增加并抑制细胞增殖。此外，用 COX-2 或 FGFR 药物抑制剂与 MET 抑制剂组合对携带 MET 抗性原位异种移植物的小鼠进行体内治疗，恢复了对 MET 抑制的敏感性，并显着抑制了肿瘤生长。这些数据揭示了对 MET 抑制剂适应性耐药的分子基础，并确定了 FDA 批准的新的可以克服耐药性的多药物治疗组合。
Glioblastoma (GBM) is the most common and most lethal primary malignant brain tumor. The receptor tyrosine kinase MET is frequently upregulated or over activated in GBM. Although clinically applicable MET inhibitors have been developed, resistance to single modality anti-MET drugs frequently occurs, rendering these agents ineffective. We aimed to determine the mechanisms of MET inhibitor resistance in GBM and use the acquired information to develop novel therapeutic approaches to overcome resistance. We investigated two clinically applicable MET inhibitors: Crizotinib, an ATP-competitive small molecule inhibitor of MET, and Onartuzumab, a monovalent monoclonal antibody that binds to the extracellular domain of the MET receptor. We developed new MET inhibitor resistant cells lines and animal models and utilized reverse phase protein arrays (RPPA) and functional assays to uncover the compensatory pathways in MET inhibitor resistant GBM. We identified critical proteins that were altered in MET inhibitor resistant GBM including mTOR, FGFR1, EGFR, STAT3 and COX-2. Simultaneous inhibition of MET and one of these upregulated proteins led to increased cell death and inhibition of cell proliferation in resistant cells compared to either agent alone. Additionally, in vivo treatment of mice bearing MET resistant orthotopic xenografts with COX-2 or FGFR pharmacological inhibitors in combination with MET inhibitor restored sensitivity to MET inhibition and significantly inhibited tumor growth. These data uncover the molecular basis of adaptive resistance to MET inhibitors and identifies new FDA-approved multi-drug therapeutic combinations that can overcome resistance.