Nefarious NTRK oncogenic fusions in pediatric sarcomas: Too many to Trk
Neurotrophic Tyrosine Receptor Kinase (NTRK) genes undergo genetic translocations to produce novel open studying frames coding for oncogenic fusion proteins the N-terminal portion, donated by various partner genes, becomes fused towards the tyrosine kinase domain of either NTRK1, NTRK2, or NTRK3. NTRK fusion proteins have being best known as driver oncogenes in a multitude of tumors in the last 30 years, including Pediatric Gliomas, Papillary Thyroid Carcinoma, Spitzoid Neoplasms, Glioblastoma, and extra tumors. Importantly, NTRK fusions work as motorists of pediatric sarcomas, comprising roughly 15% of childhood cancers including Infantile Fibrosarcoma (IFS), a subset of pediatric soft tissue sarcoma (STS). While tyrosine kinase inhibitors (TKIs), for example larotrectinib and entrectinib, have shown profound results against NTRK fusion-positive cancers, acquired potential to deal with these TKIs has led to the development of gatekeeper, solvent-front, and compound mutations. We present an extensive selection of oncogenic fusions involving NTRKs focusing particularly on pediatric STS, analyzing their biological signaling pathways and mechanisms of activation. The significance of an obligatory dimerization or multimerization domain, almost always donated through the N-terminal fusion partner, is discussed using characteristic fusions that exist in pediatric sarcomas. Additionally, examples are presented of oncogenic fusion proteins where the N-terminal partners may lead additional biological activities beyond an oligomerization domain. Lastly, therapeutic methods to treating pediatric sarcoma will be provided, using first generation and 2nd-generation agents for example selitrectinib and repotrectinib.