TRK proteins are a family of 3 transmembrane receptor tyrosine kinases (i.e. TRKA, TRKB, and TRKC) encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively [1]. Structurally, TRK proteins are 140–145 kDa in size and all TRK proteins share similar structural domains including extracellular ligand binding and intracellular kinase domains [2].
In normal neuronal tissue, TRK proteins are activated by neurotrophins, and have an essential role in nervous system development and function both in adult tissues and in embryonic development as summarised in the figure below [1-3]. The TRK – neurotrophin signaling axis has been implicated in memory formation and retention, nociception and proprioception, as well as functioning in non-neuronal tissues including the vasculature, ovaries and immune system [4].
Normal Physiological Function of TRKs [1-3]
TRK, tropomyosin receptor kinase.
Consequently on-target side effects of TRK inhibition include, weight gain, dizziness with or without ataxia, as well withdrawal pain. Other less-common neurologic complaints such as cognitive impairment, mood disorders, sleep disturbance, and dysarthria have also been reported [5].
Information regarding the management of on-target effects of TRK inhibitors is provided here.
Click here to learn more about NTRK gene fusions act as oncogenic drivers.
References
- 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.
- Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol 2018; 15: 731-747.
- Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov 2015; 5: 25-34.
- 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 1;30(Suppl_8):viii5-viii15.
- Liu D, Flory J, Lin A, Offin M, Falcon CJ, Murciano-Goroff YR, Rosen E, Guo R, Basu E, Li BT, Harding JJ, Iyer G, Jhaveri K, Gounder MM, Shukla NN, Roberts SS, Glade-Bender J, Kaplanis L, Schram A, Hyman DM, Drilon A. Characterization of on-target adverse events caused by TRK inhibitor therapy. Ann Oncol. 2020 Sep;31(9):1207-1215.