The TPM3-NTRK1 rearrangement is a recurring event in colorectal carcinoma and is associated with tumor sensitivity to TRKA kinase inhibition
Articolo
Data di Pubblicazione:
2014
Citazione:
The TPM3-NTRK1 rearrangement is a recurring event in colorectal carcinoma and is associated with tumor sensitivity to TRKA kinase inhibition / E. Ardini, R. Bosotti, A.L. Borgia, C. De Ponti, A. Somaschini, R. Cammarota, N. Amboldi, L. Raddrizzani, A. Milani, P. Magnaghi, D. Ballinari, D. Casero, F. Gasparri, P. Banfi, N. Avanzi, M.B. Saccardo, R. Alzani, T. Bandiera, E. Felder, D. Donati, E. Pesenti, A. Sartore-Bianchi, M. Gambacorta, M.A. Pierotti, S. Siena, S. Veronese, A. Galvani, A. Isacchi. - In: MOLECULAR ONCOLOGY. - ISSN 1574-7891. - 8:8(2014 Dec), pp. 1459-1507. [10.1016/j.molonc.2014.06.001]
Abstract:
The NTRK1 gene encodes Tropomyosin-related kinase A (TRKA), the high-affinity Nerve Growth Factor Receptor. NTRK1 was originally isolated from a colorectal carcinoma (CRC) sample as component of a somatic rearrangement (TPM3-NTRK1) resulting in expression of the oncogenic chimeric protein TPM3-TRKA, but there has been no subsequent report regarding the relevance of this oncogene in CRC. The KM12 human CRC cell line expresses the chimeric TPM3-TRKA protein and is hypersensitive to TRKA kinase inhibition. We report the detailed characterization of the TPM3-NTRK1 genomic rearrangement in KM12cells and through a cellular screening approach, the identification of NMS-P626, a novel highly potent and selective TRKA inhibitor. NMS-P626 suppressed TPM3-TRKA phosphorylation and downstream signaling in KM12 cells and showed remarkable antitumor activity in mice bearing KM12 tumors.Finally, using quantitative reverse transcriptase PCR and immunohistochemistry (IHC) we identified the TPM3-NTRK1 rearrangement in a CRC clinical sample, therefore suggesting that this chromosomal translocation is indeed a low frequency recurring event in CRC and that such patients might benefit from therapy with TRKA kinase inhibitors.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
Colorectal cancer; Kinase inhibitor; NMS-P626; TPM3-NTRK1 rearrangement; TRKA; Animals; Blotting, Western; Cell Line; Cell Line, Tumor; Cell Proliferation; Humans; Immunoprecipitation; In Vitro Techniques; Mice; Protein Binding; Protein Kinase Inhibitors; Receptor, trkA; Tropomyosin; Cancer Research; Genetics; Molecular Medicine
Elenco autori:
E. Ardini, R. Bosotti, A.L. Borgia, C. De Ponti, A. Somaschini, R. Cammarota, N. Amboldi, L. Raddrizzani, A. Milani, P. Magnaghi, D. Ballinari, D. Casero, F. Gasparri, P. Banfi, N. Avanzi, M.B. Saccardo, R. Alzani, T. Bandiera, E. Felder, D. Donati, E. Pesenti, A. Sartore Bianchi, M. Gambacorta, M.A. Pierotti, S. Siena, S. Veronese, A. Galvani, A. Isacchi
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