Tpr-Met, the oncogenic counterpart of the Met receptor, has been detected in gastric cancers, as well as in precursor lesions and in the adjacent normal gastric mucosa. This has prompted the suggestion that Tpr-Met may predispose to the development of gastric tumors. Given the sequence specificity of RNA interference, oncogenes activated by point mutation or rearrangements can be targeted while spearing the product of the wild-type allele. In this work, we report specific suppression of Tpr-Met expression and inhibition of Tpr-Met-mediated transformation and tumorigenesis by means of a short interfering RNA (siRNA) directed toward the Tpr-Met junction (anti-TM2). When delivered by a lentiviral vector, anti-TM2 siRNA was effective also in mouse embryonal fibroblasts or epithelial cells expressing high levels of Tpr-Met. Our results suggest that lentiviral-mediated delivery of anti-TM2 siRNA may be developed into a powerful tool to treat Tpr-Met-positive cancers.

Purpose: 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 xenogratfs. A far superior model would be a transgenic line developing spontaneous Met-driven tumors with high penetrance and short latency. Experimental Design: To this end, we introduced into the mouse genomeTPR-MET, the oncogenic form of MET.TheTpr-Met protein ensures deregulationof Met signaling because dimerization motifs in theTpr moiety cause ligand-independent activation of the Met kinase. Results: Here, we describe aTPR-MET transgenic line that develops thymicT-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. Conclusions: 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.Targeted approaches are expected to revolutionize cancer treatment in the near future (1). Receptor tyrosine kinases are among the most actively pursued targets (2). To date, a number of small molecule inhibitors (generally ATP analogues) are already either approved (3) or undergoing clinical trials (2). Although treatment with specific inhibitors may result in resistance due to mutations in the target (4) or to amplification of other receptor genes (5), this can be bypassed by using them in combination or together with other molecular tools.Met is the tyrosine kinase receptor for hepatocyte growth factor (HGF)/scatter factor. This ligand/receptor pair is involved in cell survival, proliferation, and migration (6). Deregulated Met activation has been linked to cancer predisposition and metastasis (6 -8), and frequently correlates with poor prognosis in carcinomas, sarcomas, and hematological cancers (7). The potential involvement in such a vast array of cancers has stimulated the search for Met inhibitors (9). Recent results suggest that subsets of patients with gastric (10) or lung cancers (5) with Met amplification may be appropriate for clinical trials with Met inhibitors. Thus, there is a need of animal models for preclinical testing of such compounds. Thus far, this has been done in nude mice transplanted with tumor c...