Accornero Paolo, Lattanzio Giuseppe, Mangano Tony, Chiarle Roberto, Taulli Riccardo, Bersani Francesca, Forni Paolo E, Miretti Silvia, Scuoppo Claudio, Dastrù Walter, Christensen James G, Crepaldi Tiziana, Ponzetto Carola
Department of Anatomy, Pharmacology, and Forensic Medicine, University of Torino,Torino, Italy.
Clin Cancer Res. 2008 Apr 1;14(7):2220-6. doi: 10.1158/1078-0432.CCR-07-2064.
Met, the tyrosine kinase receptor for hepatocyte growth factor, is frequently deregulated in human cancer. Recent evidence indicates that Met amplification may confer resistance to treatments directed toward other receptor tyrosine kinases. Thus, there is a need to develop Met inhibitors into therapeutic tools, to be used alone or in combination with other molecularly targeted drugs. Preclinical validation of Met inhibitors has thus far been done in nude mice bearing cancer cells xenografts. A far superior model would be a transgenic line developing spontaneous Met-driven tumors with high penetrance and short latency.
To this end, we introduced into the mouse genome TPR-MET, the oncogenic form of MET. The Tpr-Met protein ensures deregulation of Met signaling because dimerization motifs in the Tpr moiety cause ligand-independent activation of the Met kinase.
Here, we describe a TPR-MET transgenic line that develops thymic T-cell lymphoma with full penetrance and very short latency. In the tumors, Tpr-Met and its effectors were phosphorylated. Treatment of tumor-derived T lymphocytes with the selective Met inhibitor PHA-665752 at nanomolar concentrations abolished phosphorylation of Met and downstream effectors and led to caspase-mediated apoptosis. I.v. administration of PHA-665752 to transgenic mice bearing lymphomas in exponential growth phase led to a significant decrease in tumor growth and, in some cases, to tumor regression.
Our transgenic line, which within 2 months reliably develops Tpr-Met-driven T-cell lymphoma, represents a valuable tool to explore the efficacy and therapeutic potential of Met kinase inhibitors as anticancer drugs.
Met作为肝细胞生长因子的酪氨酸激酶受体，在人类癌症中经常失调。最近的证据表明，Met扩增可能导致对针对其他受体酪氨酸激酶的治疗产生耐药性。因此，有必要将Met抑制剂开发成治疗工具，单独使用或与其他分子靶向药物联合使用。到目前为止，Met抑制剂的临床前验证是在携带癌细胞异种移植的裸鼠中进行的。一个更优越的模型将是一个转基因品系，它能自发地发展出具有高发病率和短潜伏期的Met驱动的肿瘤。
为此，我们将MET的致癌形式TPR-MET引入小鼠基因组。Tpr-Met蛋白确保Met信号失调，因为Tpr部分中的二聚化基序导致Met激酶的配体非依赖性激活。
在这里，我们描述了一个TPR-MET转基因品系，它能以完全的发病率和非常短的潜伏期发展出胸腺T细胞淋巴瘤。在肿瘤中，Tpr-Met及其效应器被磷酸化。用纳摩尔浓度的选择性Met抑制剂PHA-665752处理肿瘤来源的T淋巴细胞，消除了Met和下游效应器的磷酸化，并导致半胱天冬酶介导的凋亡。对处于指数生长期的携带淋巴瘤的转基因小鼠静脉注射PHA-665752导致肿瘤生长显著减少，在某些情况下导致肿瘤消退。
我们的转基因品系在2个月内可靠地发展出Tpr-Met驱动的T细胞淋巴瘤，是探索Met激酶抑制剂作为抗癌药物的疗效和治疗潜力的有价值工具。
