NTRK gene fusions are targetable driver genomic alterations. These code for fusion proteins and drive tumorigenesis [1-3].
All identified NTRK gene fusions involve joining of the 3’ region of the NTRK gene, including the kinase domain, with the 5’ region of a different gene (i.e. the fusion partner) by intra- or inter-chromosomal rearrangement [1, 4].
NTRK Gene Fusion Structure
The protein resulting from transcription and translation of the fusion is a chimeric oncoprotein. This oncoprotein is characterised by ligand-independent continual activation and overexpression of the TRK protein kinase [1, 4]. The TRK protein kinase domain is always present in TRK fusion proteins . In contrast, the transmembrane domain is not present in all TRK protein fusions, suggesting it is not required for kinase activation but perhaps has a different function (e.g., cellular localisation) .
TRK Fusion Protein Structure
The resulting fusion protein is oncogenic and results in constitutive activation of signalling pathways including the MAPK, PI3K and PKC pathway [5,6].
The figure below (adapted for ) shows different gene fusions (>100) that have been described involving the three NTRK and partner genes across several tumour types.
Click here to find out more on the epidemiology of cancers with NTRK gene fusion.
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