Affiliation:
1. Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland
2. Helsinki Institute of Life Science, University of Helsinki, 00014 Helsinki, Finland
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.
Funder
Academy of Finland
Sigrid Jusélius Foundation
Finnish Cancer Foundation
University of Helsinki Three-year Research Grant
Biocentrum Helsinki, Biocentrum Finland, HiLIFE, Magnus Ehrnrooth Foundation
Instrumentarium Research Foundation
Cited by
3 articles.
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