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Review
. 2019 Nov 1;30(Suppl_8):viii5-viii15.
doi: 10.1093/annonc/mdz383.

Tropomyosin receptor kinase (TRK) biology and the role of NTRK gene fusions in cancer

A Amatu  1 , A Sartore-Bianchi  1   2 , K Bencardino  1 , E G Pizzutilo  1   2 , F Tosi  1   2 , S Siena  1   2
Affiliations
Review

Tropomyosin receptor kinase (TRK) biology and the role of NTRK gene fusions in cancer

A Amatu et al. Ann Oncol. .

Abstract

The tropomyosin receptor kinase (TRK) family of receptor tyrosine kinases are encoded by NTRK genes and have a role in the development and normal functioning of the nervous system. Since the discovery of an oncogenic NTRK gene fusion in colorectal cancer in 1986, over 80 different fusion partner genes have been identified in a wide array of adult and paediatric tumours, providing actionable targets for targeted therapy. This review describes the normal function and physiology of TRK receptors and the biology behind NTRK gene fusions and how they act as oncogenic drivers in cancer. Finally, an overview of the incidence and prevalence of NTRK gene fusions in various types of cancers is discussed.

Keywords: NTRK gene fusions; TRK; TRK fusion cancer; tropomyosin receptor kinase.

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Figures

Figure 1.
Figure 1.
Structure of TRK receptors and interaction with ligands [5]. The neurotrophins display specific interactions with the three TRK receptors: NGF binds TRKA, BDNF and NT-4 bind TRKB and NT-3 binds TRKC. NT-3 can also activate TRKA and TRKB albeit with less efficiency. BDNF, brain-derived neurotrophic factor; C1/C2, cysteine-rich clusters; Ig1/Ig2, immunoglobulin-like domains; LRR1–3, leucine-rich repeats; NGF, nerve growth factor; NT-3/4, neurotrophin 3/4; TRK, tropomyosin receptor kinase.
Figure 2.
Figure 2.
Known splice variants of TRKA, TRKB and TRKC [6]. C1/C2, cysteine-rich clusters; Ig1/Ig2, immunoglobulin-like domains; KD, kinase domain; LRR1–3, leucine-rich repeats; TM, transmembrane; TRK, tropomyosin receptor kinase.
Figure 3.
Figure 3.
TRK signalling pathway. (A) Overview of TRK signalling pathway; (B) activation of TRKA. C1/C2, cysteine-rich clusters; Ig1/Ig2, immunoglobulin-like domains; LRR1–3, leucine-rich repeats; NGF, nerve growth factor; TRK, tropomyosin receptor kinase, TRKi, tropomyosin receptor kinase inhibitor.
Figure 4.
Figure 4.
NTRK gene fusions in cancers. *Sinonasal low-grade non-intestinal-type adenocarcinoma, parotid gland acinic cell carcinoma, anaplastic thyroid carcinoma, Erdheim–Chester disease, interdigitating dendritic cell sarcoma. **One large-cell neuroendocrine carcinoma of the lung with COP1-NTRK1, one small-cell lung cancer with ETV6-NTRK3. CMN, congenital mesoblastic nephroma; GIST, gastrointestinal stromal tumour; ICC, intrahepatic cholangiocarcinoma; IFS, infantile fibrosarcoma; MASC, mammary analogue secretory carcinoma; NET, neuroendocrine tumour; NSCLC, non-small-cell lung cancer.
See this image and copyright information in PMC

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