The TPM3-NTRK1 rearrangement is a recurring event in colorectal carcinoma and is associated with tumor sensitivity to TRKA kinase inhibition
| Autor: | Arturo Galvani, Rosaria Cammarota, Silvio Veronese, Andrea Sartore-Bianchi, Andrea Lombardi Borgia, Fabio Gasparri, Laura Raddrizzani, Marco A. Pierotti, Marcello Gambacorta, Enrico Pesenti, Dario Ballinari, Nadia Amboldi, Paola Magnaghi, Salvatore Siena, Nilla Avanzi, Alessio Somaschini, Eduard R. Felder, Elena Ardini, Tiziano Bandiera, Maria Beatrice Saccardo, Cristina De Ponti, Daniele Casero, Andrea Milani, Roberta Bosotti, Rachele Alzani, Patrizia Banfi, Antonella Isacchi, Daniele Donati |
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| Rok vydání: | 2014 |
| Předmět: |
Cancer Research
animal structures Blotting Western Entrectinib Tropomyosin Tropomyosin receptor kinase A Biology In Vitro Techniques Cell Line Mice Cell Line Tumor Genetics Animals Humans Immunoprecipitation Receptor trkA Protein Kinase Inhibitors Research Articles Cell Proliferation Oncogene Kinase Cell growth General Medicine Fusion protein Molecular biology Oncology nervous system Cancer research Molecular Medicine Phosphorylation Immunohistochemistry Protein Binding |
| Zdroj: | Molecular oncology. 8(8) |
| ISSN: | 1878-0261 |
| Popis: | 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 KM12 cells 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. |
| Databáze: | OpenAIRE |
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