An in vivo model of Met-driven lymphoma as a tool to explore the therapeutic potential of Met inhibitors.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


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.
Accornero
Paolo
P
Department of Anatomy, Pharmacology, and Forensic Medicine, University of Torino,Torino, Italy.
Lattanzio
Giuseppe
G
Mangano
Tony
T
Chiarle
Roberto
R
Taulli
Riccardo
R
Bersani
Francesca
F
Forni
Paolo E
PE
Miretti
Silvia
S
Scuoppo
Claudio
C
Dastrù
Walter
W
Christensen
James G
JG
Crepaldi
Tiziana
T
Ponzetto
Carola
C
D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology; D008223:Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000187:drug effects / Q000235:genetics*; D013450:Sulfones / Q000494:pharmacology
C480541:5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one; D007211:Indoles; D047428:Protein Kinase Inhibitors; D013450:Sulfones; D019859:Proto-Oncogene Proteins c-met