2. Academic Validation
  3. The Impact of ETV6-NTRK3 Oncogenic Gene Fusions on Molecular and Signaling Pathway Alterations

The Impact of ETV6-NTRK3 Oncogenic Gene Fusions on Molecular and Signaling Pathway Alterations

  • Cancers (Basel). 2023 Aug 24;15(17):4246. doi: 10.3390/cancers15174246.
Matias Kinnunen 1 2,  Xiaonan Liu 1 2,  Elina Niemelä 1 2,  Tiina Öhman 1 2,  Lisa Gawriyski 1 2,  Kari Salokas 1 2,  Salla Keskitalo 1 2,  Markku Varjosalo 1 2
Affiliations

Affiliations

  • 1 Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland.
  • 2 Helsinki Institute of Life Science, University of Helsinki, 00014 Helsinki, Finland.
PMID: 37686522 DOI: 10.3390/cancers15174246
Abstract

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.

Keywords

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

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