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

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.

A Human IgSF Cell-Surface Interactome Reveals a Complex Network of Protein-Protein Interactions

“…High-affinity nerve growth factor receptor (NTRK1), also known as TrkA, has multiple well-studied functions in the nervous system (Amatu et al, 2019). In the immune system, where its function is not well understood, TrkA is expressed on monocytes, macrophages, dendritic cells, resting and activated B cells and neutrophils, and erythroblasts (Minnone et al, 2017).…”

Entrectinib approval by EMA reinforces options for ROS1 and tumour agnostic NTRK targeted cancer therapies

“…11 The clinical benefit observed with a partial response achieved after 1 month of treatment in the first patient with NTRK fusion-positive colorectal cancer enrolled represented the first clinical proof of concept validation of NTRK fusions as targets for therapy in patients with colorectal cancer and spurred the search of such rearrangements in many additional tumour types. [12][13][14] Both Ignyta, a US biotech company that in 2013 acquired the rights for the development of entrectinib, and Roche that after the acquisition of Ignyta in 2017 developed the molecule up to the registration, have continued with wilfulness and determination the clinical exploration of entrectinib activity across many different NTRK fusion-positive tumour types. These joint efforts resulted, as already mentioned, in the tumour-agnostic approval of entrectinib and most importantly to high and durable therapeutic benefits for most of the treated patients.…”

Neurotrophic receptor tyrosine kinase (NTRK) fusions and their role in cancer

“…NTRK fusions have been identified in both low‐grade and high‐grade gliomas, with a greater frequency of 40% in patients aged <3 years who present with nonbrainstem high‐grade gliomas but an overall rate of approximately 4% in unselected cohorts of pediatric gliomas 15,16 . Although NTRK fusions have also been identified in mixed glioneuronal tumors, NTRK fusions have not been detected in medulloblastoma or ependymoma 15 …”

“…The ETV6‐NTRK3 fusion has been found in almost all cases of congenital mesoblastic nephroma, displaying the cellular and mixed histologic subtypes, but not in the classic subtype, and have been shown to co‐occur with trisomy 11 7,16 …”