Abstract 4265: Identification of new NTRK1 gene fusion as oncogene target in colon cancer

In an effort to better characterize the activity of a multi-kinase inhibitors, antiproliferative activity was evaluated against a panel of human tumor cell lines. Among the different cell lines tested we have been able to highlight that the KM12 human colorectal carcinoma present hypersensitivity to inhibition. By intersecting the results of activity of the compound and the bibliographic data, we could confirm that the activity of the compound was mediated by the inhibition of phosphorylation of the receptor NTRK1. The NTRK1 gene encodes Tropomyosin-related kinase A (TRKA), the hight-affinity Nerve Growth Factor Receptor. NTRK1 was originally isolated from a human colon carcinoma as a transforming oncogene activated by a somatic rearrangement that fused TPM3 (non-muscle tropomyosin) gene to kinase domain of a novel tyrosine-kinase receptor. The KM12 human CRC cell line expresses the chimeric TPM3-TRKA protein and is hypersensitive to TRKA kinase inhibition. Using differential quantitative reverse transcriptase PCR and optimised immunohistochemistry we could confirm the existence of low frequency (0.5%) NTRK1 re-arranged / activated forms in colorectal carcinoma. A same colorectal tumor sample could contain different fusion transcripts, highlighting the molecular heterogeneity of this type of tumor Furthermore we detect a novel NTRK1 fusion in colorectal carcinoma clinical samples corresponding to oncogenic rearrangement TRK-T2 identified in papillary thyroid carcinoma. These results confirm the potential interest of the target NTRK1 in the panel of targeted therapies against colorectal cancer. Citation Format: Laurent Creancier, Caroline Dejean, Isabelle Vandenberghe, Jean-Christophe Blanchet, Yannick Aussagues, Jean Philippe Annereau, Janick Selves, Anna Kruczynski. Identification of new NTRK1 gene fusion as oncogene target in colon cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4265. doi:10.1158/1538-7445.AM2015-4265