NTRK gene fusions as novel targets of cancer therapy across multiple tumour types

Abstract

The tropomyosin receptor kinase (Trk) receptor family comprises 3 transmembrane proteins referred to as Trk A, B and C (TrkA, TrkB and TrkC) receptors that are encoded by the NTRK1, NTRK2 and NTRK3 genes, respectively. These receptor tyrosine kinases are expressed in human neuronal tissue and play an essential role in the physiology of development and function of the nervous system through activation by neurotrophins. Gene fusions involving NTRK genes lead to transcription of chimeric Trk proteins with constitutively activated or overexpressed kinase function conferring oncogenic potential. These genetic abnormalities have recently emerged as targets for cancer therapy, because novel compounds have been developed that are selective inhibitors of the constitutively active rearranged proteins. Developments in this field are being aided by next generation sequencing methods as tools for unbiased gene fusions discovery. In this article, we review the role of NTRK gene fusions across several tumour histologies, and the promises and challenges of targeting such genetic alterations for cancer therapy.

Keywords: Molecular oncology; NTRK; Target therapy; gene fusions.

Figure 1

Schematic view of Trk receptors signalling, showing the three major pathways involved in cell differentiation and survival. AKT, v-akt murine thymoma viral oncogene homologue; BDGF, brain-derived growth factor; DAG, diacyl-glycerol; ERK, extracellular signal-regulated kinase; GAB1, GRB2-associated-binding protein 1; GRB2, growth factor receptor-bound protein 2; IP3, inositol trisphosphate; MEK, mitogen-activated protein kinase; NGF, nerve growth factor; NTF-3, neurotrophin 3; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PKC, protein kinase C; PLC, phospholipase C; RAF, rapidly accelerated fibrosarcoma kinase; RAS, rat sarcoma kinase; SHC, Src homology 2 domain containing.

Figure 2

The chimeric Trk protein, composed by the TK domain with ATPase activity and a TM loop along with a fusion partner. Oligomerisation of the chimeric protein is the main proposed mechanisms for increased tumour cell survival and proliferation via the known pathways of Trk receptors. (A) NTRK1 gene with 17 exon sequences and respective TrkA protein regions. (B) Mechanism of entrectinib (E) action and the known mechanisms of acquired resistance (point mutation G595R and G567C) to E. Cys, cysteine clusters; Ig1 and Ig2, first and second immunoglobulin-like motifs, respectively; LRM, leucine-rich motifs; SP, signal peptide; TK, tyrosine kinase; TM, transmembrane.