The oncogenic neurotrophin receptor tropomyosin-related kinase variant, TrkAIII

Abstract

Oncogenes derived from the neurotrophin receptor tropomyosin-related kinase TrkA act as drivers in sub-populations of a wide-range of human cancers. This, combined with a recent report that both adult and childhood cancers driven by novel oncogenic TrkA chimeric-fusions exhibit profound, long-lived therapeutic responses to the Trk inhibitor Larotrectinib, highlights the need to improve clinical detection of TrkA oncogene-driven cancers in order to maximise this novel therapeutic potential. Cancers potentially driven by TrkA oncogenes include a proportion of paediatric neuroblastomas (NBs) that express the alternative TrkA splice variant TrkAIII, which exhibits exon 6, 7 and 9 skipping and oncogenic-activity that depends upon deletion of the extracellular D4 Ig-like domain. In contrast to fully spliced TrkA, which exhibits tumour suppressor activity in NB and associates with good prognosis, TrkAIII associates with advanced stage metastatic disease, post therapeutic relapse and worse prognosis, induces malignant transformation of NIH-3T3 cells and exhibits oncogenic activity in NB models. TrkAIII induction in NB cells is stress-regulated by conditions that mimic hypoxia or perturbate the ER with potential to change TrkA tumour-suppressing signals into oncogenic TrkAIII signals within the stressful tumour microenvironment. In contrast to cell surface TrkA, TrkAIII re-localises to intracellular pre-Golgi membranes, centrosomes and mitochondria, within which it exhibits spontaneous ligand-independent activation, triggering a variety of mechanisms that promote tumorigenicity and malignant behaviour, which impact the majority of cancer hallmarks. In this review, we present updates on TrkAIII detection and association with human malignancies, the multiple ways TrkAIII exerts oncogenic activity and potential therapeutic approaches for TrkAIII expressing cancers, with particular reference to NB.

Immunoexpression of BDNF, TrkB, and p75NTR receptors in peripheral neural lesions of the head and neck

“…14 TrkB belongs to the family of receptor tyrosine kinases (RTKs) and it is believed that some RTKs may act as oncogenes. 33 Our findings showed that TrkB was strongly present in TN, NF, SC, and MPNST, and slightly expressed in GCT. Its high expression confirms what we observed for BDNF and the high affinity of its binding.…”

Two Receptors, Two Isoforms, Two Cancers: Comprehensive Analysis of KIT and TrkA Expression in Neuroblastoma and Acute Myeloid Leukemia

“…Also, Plexin C1 is involved in melanoma progression, its expression is absent in the early stages of the melanoma but occurs in late stages as a pro-survival and anti-apoptotic factor marker and acts via the activation of AKT pathway (81). Interestingly TrkA is considered to be a potential oncogene in malignant melanoma (33), and predominant TrkAIII expression has been detected in metastatic melanoma (39). That may point to the existence of the connection between NTRK1 and PLXCN1 expression in malignant diseases.…”

“…Ectopic expression of the RUNX1-RUNX1T fusion gene, formed as a result of t(8;21) translocation common in pediatric AML, in CD34+ hematopoietic cells induces TrkA expression (37). Recently it was shown that an oncogenic TrkAIII splice isoform was expressed in the thymus and cutaneous melanomas, as well as in the Jurkat T-ALL cell line (38, 39).…”

NTRK Fusions in Central Nervous System Tumors: A Rare, but Worthy Target

“…The true oncogenic potential of non-fusion NTRK alterations, such as mutations, gene amplifications and alternative splicing has yet to be confirmed [49,50,[82][83][84][85][86]. Moreover, as it will be furtherly discussed later, these alternative types of alterations can play a crucial role in tumor resistance against NTRK-fusions inhibitors and therefore are being increasingly investigated [70,87].…”