NTRK Gene Fusions

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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 [1]. 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) [1].

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 [6]) 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.

References

1. Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol 2018; 15: 731-747.
2. Stransky N, Cerami E, Schalm S et al. The landscape of kinase fusions in cancer. Nat Commun 2014; 5: 4846.
3. Chen Y, Chi P. Basket trial of TRK inhibitors demonstrates efficacy in TRK fusion-positive cancers. J Hematol Oncol 2018; 11: 78.
4. Amatu A, Sartore-Bianchi A, Siena S. NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open 2016; 1: e000023.
5. Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov 2015; 5: 25-34.
6. Amatu A, Sartore-Bianchi A, Bencardino K, Pizzutilo EG, Tosi F, Siena S. Tropomyosin receptor kinase (TRK) biology and the role of NTRK gene fusions in cancer. Ann Oncol. 2019; Nov 30 Suppl 8:viii5-viii15.