A novel TRKB-activating internal tandem duplication characterizes a new mechanism of receptor tyrosine kinase activation
Details
Publication Year 2025-05-10,Volume 9,Issue #1,Page 137
Journal Title
NPJ Precision Oncology
Publication Type
Research article
Abstract
Precision medicine programs like the Zero Childhood Cancer Program perform comprehensive molecular analysis of patient tumors, enabling detection of novel structural variants that may be cryptic to standard techniques. Identification of these variants can impact individual patient treatment, and beyond this establish new mechanisms of oncogenic activation. We have identified a novel internal tandem duplication (ITD) in the receptor tyrosine kinase (RTK), NTRK2, in a patient with FOXR2-activated CNS neuroblastoma. The ITD spans exons 10-13 of NTRK2 encoding the transmembrane domain. NTRK2 ITD is transforming and sensitive to TRK inhibition. In silico structural predictions suggested the duplication of an alpha-helix region and juxtaposed tyrosine residues that play a role in facilitating autophosphorylation. Consistent with this, mutation of these residues inhibited cellular transformation. This is the first report of an ITD spanning the transmembrane domain of an RTK, characterizing an additional mechanism by which RTKs are activated in cancer.
Publisher
Springer Nature
Department(s)
Laboratory Research
Open Access at Publisher's Site
https://doi.org/10.1038/s41698-025-00928-3
Terms of Use/Rights Notice
Refer to copyright notice on published article.


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