Ntrk3, also known as the neurotrophin-3 receptor, encodes a protein tyrosine kinase. It is involved in multiple signaling cascades, such as the Ras-MAP kinase and PI3K-AKT pathways through the IRS-1 adapter protein [4]. Ntrk3 has pleiotropic functions, acting as an oncogene in some cancers like breast and gastric cancers, and as a dependence receptor in tumor suppressor genes in colon cancer and neuroblastomas [6]. It also plays a role in the regulation of gonadotrope cell adhesion and motility through the Neurod1/4-Ntrk3-cSrc pathway [8].

Ntrk3 gene fusions are oncogenic drivers in various cancers. The ETV6-Ntrk3 (TEL-TRKC) gene fusion, associated with congenital fibrosarcoma, encodes a chimeric oncoprotein with transformation activity in multiple cell lineages [4]. In breast, salivary gland (secretory carcinomas), prostatic acinar adenocarcinoma, and ganglioglioma, Ntrk3 gene fusions have been identified as drivers or rare molecular events [1,2,3,5]. In upper tract urothelial carcinomas, higher Ntrk3 expression is correlated with worse survival outcomes, and it may interact with the PI3K-AKT-mTOR signaling pathway to promote cancer [6]. In Spitz tumours, Ntrk3 fusions expand the range of oncogenic kinase fusions in melanocytic neoplasms [7].

In conclusion, Ntrk3 is crucial in multiple biological processes and is significantly involved in various disease conditions, especially cancer. The discovery of Ntrk3 gene fusions in different cancers highlights its importance as a potential therapeutic target. Understanding Ntrk3's role through gene-based research models helps in developing more targeted treatment strategies for these cancers.