Journal
MOLECULAR ONCOLOGY
Volume 8, Issue 8, Pages 1495-1507Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.molonc.2014.06.001
Keywords
TPM3-NTRK1 rearrangement; TRKA; Kinase inhibitor; NMS-P626; Colorectal cancer
Categories
Funding
- Associazione Italiana Ricerca Cancro (AIRC) [AIRC 5 x 1000, 5 x 1000]
- Grant Molecular therapies of Solid Tumors from Oncologia Ca' Granda Onlus (OCGO) Fondazioneldquo
Ask authors/readers for more resources
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. (C) 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available