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

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 h...

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Bibliographic Details
Published in:Cancers 2023-08, Vol.15 (17), p.4246
Main Authors: Kinnunen, Matias, Liu, Xiaonan, Niemelä, Elina, Öhman, Tiina, Gawriyski, Lisa, Salokas, Kari, Keskitalo, Salla, Varjosalo, Markku
Format: Article
Language:English
Subjects:
Cancer
Chromosome translocations
Comparative analysis
ErbB protein
Ethylenediaminetetraacetic acid
Fusion protein
Genes
Genetic transcription
Hematology
Ions
Kinases
Leukemia
Mass spectrometry
Mass spectroscopy
Neurotrophin 3
Peptides
Protein-tyrosine kinase
Proteins
Proteomics
Scientific imaging
Signal transduction
Tumorigenesis
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Summary: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.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers15174246