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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].

Figure 3: NTRK Gene Fusion Structure

Figure 3: 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].

Figure 4: TRK Fusion Protein Structure

Figure 4: 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].

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.

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