Chromosomal translocations creating fusion genes are common cancer drivers. The oncogenic ETV6-NTRK3 (EN) gene fusion joins the sterile alpha domain of the ETV6 transcription factor with the tyrosine kinase domain of the neurotrophin-3 receptor NTRK3. Four EN variants with alternating break points have since been detected in a wide range of human cancers. To provide molecular level insight into EN oncogenesis, we employed a proximity labeling mass spectrometry approach to define the molecular context of the fusions. We identify in total 237 high-confidence interactors, which link EN fusions to several key signaling pathways, including ERBB, insulin and JAK/STAT. We then assessed the effects of EN variants on these pathways, and showed that the pan NTRK inhibitor Selitrectinib (LOXO-195) inhibits the oncogenic activity of EN2, the most common variant. This systems-level analysis defines the molecular framework in which EN oncofusions operate to promote cancer and provides some mechanisms for therapeutics.

Original languageEnglish
Article number4246
Issue number17
Publication statusPublished - Sep 2023
MoE publication typeA1 Journal article-refereed

Bibliographical note

Funding Information:
This study was supported by grants from the Academy of Finland (nos. 288475, 294173, and 350225), the Sigrid Jusélius Foundation, the Finnish Cancer Foundation, the University of Helsinki Three-year Research Grant, Biocentrum Helsinki, Biocentrum Finland, HiLIFE, Magnus Ehrnrooth Foundation, and the Instrumentarium Research Foundation.

Publisher Copyright:
© 2023 by the authors.

Fields of Science

  • BioID
  • biotin proximity labeling
  • breakpoint variant
  • ETV6-NTRK3
  • gene fusion
  • interaction analysis
  • mass spectrometry
  • proteomics

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