Crizotinib inhibits NF2-associated schwannoma through inhibition of focal adhesion kinase 1.
Crizotinib inhibits NF2-associated schwannoma through inhibition of focal adhesion kinase 1.
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DOI：
10.18632/oncotarget.10248
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发表时间：
2016-08-23
期刊：
影响因子：
--
通讯作者：
Kissil JL
中科院分区：
文献类型：
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作者：
Troutman S;Moleirinho S;Kota S;Nettles K;Fallahi M;Johnson GL;Kissil JL
2型神经纤维瘤病（NF2）是一种以第八脑神经神经鞘瘤为特征的显性遗传常染色体疾病。NF2肿瘤抑制基因编码Merlin，这是一种涉及多种细胞信号通路的抑制蛋白。为了确定nf2相关恶性肿瘤的潜在药物靶点，我们评估了抑制酪氨酸激酶受体MET的后果。我们发现克唑替尼，一种MET和ALK抑制剂，是一种有效的体外抑制NF2-null雪旺细胞增殖和体内肿瘤生长的抑制剂。为了确定克唑替尼的靶点/s，我们采用了基于活性的蛋白谱分析（ABPP），从而确定FAK1 （PTK2）是克唑替尼抑制nf2缺失神经鞘瘤细胞的相关靶点。随后的研究证实，抑制FAK1足以抑制NF2动物模型中的肿瘤发生，并且耐克里唑替尼形式的FAK1可以挽救治疗效果。这些研究确定了一种FDA批准的药物作为NF2的潜在治疗方法，并描述了NF2缺失雪旺细胞的作用机制。
Neurofibromatosis type 2 (NF2) is a dominantly inherited autosomal disease characterized by schwannomas of the 8th cranial nerve. The NF2 tumor suppressor gene encodes for Merlin, a protein implicated as a suppressor of multiple cellular signaling pathways. To identify potential drug targets in NF2-associated malignancies we assessed the consequences of inhibiting the tyrosine kinase receptor MET. We identified crizotinib, a MET and ALK inhibitor, as a potent inhibitor of NF2-null Schwann cell proliferation in vitro and tumor growth in vivo. To identify the target/s of crizotnib we employed activity-based protein profiling (ABPP), leading to identification of FAK1 (PTK2) as the relevant target of crizotinib inhibition in NF2-null schwannoma cells. Subsequent studies confirm that inhibition of FAK1 is sufficient to suppress tumorigenesis in animal models of NF2 and that crizotinib-resistant forms of FAK1 can rescue the effects of treatment. These studies identify a FDA approved drug as a potential treatment for NF2 and delineate the mechanism of action in NF2-null Schwann cells.