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.
| Original language | English |
|---|---|
| Article number | 4246 |
| Journal | Cancers |
| Volume | 15 |
| Issue number | 17 |
| ISSN | 2072-6694 |
| DOIs | |
| Publication status | Published - Sep 2023 |
| MoE publication type | A1 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