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.
Titolo: | The TPM3-NTRK1 rearrangement is a recurring event in colorectal carcinoma and is associated with tumor sensitivity to TRKA kinase inhibition |
Autori: | |
Parole Chiave: | 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 |
Settore Scientifico Disciplinare: | Settore MED/06 - Oncologia Medica |
Data di pubblicazione: | dic-2014 |
Rivista: | |
Tipologia: | Article (author) |
Digital Object Identifier (DOI): | 10.1016/j.molonc.2014.06.001 |
Appare nelle tipologie: | 01 - Articolo su periodico |
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