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Updated: May 14, 2025

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A novel TRKB-activating internal tandem duplication characterizes a new mechanism of receptor tyrosine kinase

Lauren M Brown1,2, Gabor Tax1,2, Pablo Acera Mateos1,2

  • 1Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia.

NPJ Precision Oncology
|May 10, 2025
PubMed

Insights

Researchers discovered a new internal tandem duplication (ITD) in the NTRK2 gene, a receptor tyrosine kinase (RTK), in a pediatric brain tumor. This finding reveals a novel cancer-driving mechanism and potential therapeutic target for TRK inhibitors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Precision medicine utilizes comprehensive molecular tumor analysis to identify actionable targets.
  • Novel structural variants, including internal tandem duplications (ITDs), can drive oncogenesis but may be missed by standard methods.

Purpose of the Study:

  • To identify and characterize novel structural variants in pediatric tumors.
  • To investigate the functional impact of a newly identified NTRK2 internal tandem duplication (ITD).

Main Methods:

  • Comprehensive molecular analysis of patient tumors.
  • In silico structural prediction of the identified NTRK2 ITD.
  • Functional assays to assess cellular transformation and sensitivity to TRK inhibition.

Main Results:

  • A novel ITD spanning exons 10-13 of NTRK2, encoding the transmembrane domain, was identified in a FOXR2-activated CNS neuroblastoma.
  • The NTRK2 ITD was found to be transforming and sensitive to TRK inhibition.
  • In silico analysis suggested the ITD promotes autophosphorylation via duplicated alpha-helix and juxtaposed tyrosine residues; mutation of these residues abrogated transformation.

Conclusions:

  • This study reports the first ITD within the transmembrane domain of a receptor tyrosine kinase (RTK).
  • The identified NTRK2 ITD represents a new mechanism of RTK activation in cancer.
  • This finding has implications for targeted therapy in specific pediatric cancers.

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