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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| Format: | Article |
| Language: | English |
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MDPI AG
2023-08-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/17/4246 |
| _version_ | 1797582721401225216 |
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| author | Matias Kinnunen Xiaonan Liu Elina Niemelä Tiina Öhman Lisa Gawriyski Kari Salokas Salla Keskitalo Markku Varjosalo |
| author_facet | Matias Kinnunen Xiaonan Liu Elina Niemelä Tiina Öhman Lisa Gawriyski Kari Salokas Salla Keskitalo Markku Varjosalo |
| author_sort | Matias Kinnunen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T23:26:32Z |
| format | Article |
| id | doaj.art-3402565ad7c54bffa399ae262236776e |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T23:26:32Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-3402565ad7c54bffa399ae262236776e2023-11-19T07:55:10ZengMDPI AGCancers2072-66942023-08-011517424610.3390/cancers15174246The Impact of ETV6-NTRK3 Oncogenic Gene Fusions on Molecular and Signaling Pathway AlterationsMatias Kinnunen0Xiaonan Liu1Elina Niemelä2Tiina Öhman3Lisa Gawriyski4Kari Salokas5Salla Keskitalo6Markku Varjosalo7Institute of Biotechnology, University of Helsinki, 00014 Helsinki, FinlandInstitute of Biotechnology, University of Helsinki, 00014 Helsinki, FinlandInstitute of Biotechnology, University of Helsinki, 00014 Helsinki, FinlandInstitute of Biotechnology, University of Helsinki, 00014 Helsinki, FinlandInstitute of Biotechnology, University of Helsinki, 00014 Helsinki, FinlandInstitute of Biotechnology, University of Helsinki, 00014 Helsinki, FinlandInstitute of Biotechnology, University of Helsinki, 00014 Helsinki, FinlandInstitute of Biotechnology, University of Helsinki, 00014 Helsinki, FinlandChromosomal 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.https://www.mdpi.com/2072-6694/15/17/4246ETV6-NTRK3gene fusionbreakpoint variantproteomicsinteraction analysismass spectrometry |
| spellingShingle | Matias Kinnunen Xiaonan Liu Elina Niemelä Tiina Öhman Lisa Gawriyski Kari Salokas Salla Keskitalo Markku Varjosalo The Impact of ETV6-NTRK3 Oncogenic Gene Fusions on Molecular and Signaling Pathway Alterations Cancers ETV6-NTRK3 gene fusion breakpoint variant proteomics interaction analysis mass spectrometry |
| title | The Impact of ETV6-NTRK3 Oncogenic Gene Fusions on Molecular and Signaling Pathway Alterations |
| title_full | The Impact of ETV6-NTRK3 Oncogenic Gene Fusions on Molecular and Signaling Pathway Alterations |
| title_fullStr | The Impact of ETV6-NTRK3 Oncogenic Gene Fusions on Molecular and Signaling Pathway Alterations |
| title_full_unstemmed | The Impact of ETV6-NTRK3 Oncogenic Gene Fusions on Molecular and Signaling Pathway Alterations |
| title_short | The Impact of ETV6-NTRK3 Oncogenic Gene Fusions on Molecular and Signaling Pathway Alterations |
| title_sort | impact of etv6 ntrk3 oncogenic gene fusions on molecular and signaling pathway alterations |
| topic | ETV6-NTRK3 gene fusion breakpoint variant proteomics interaction analysis mass spectrometry |
| url | https://www.mdpi.com/2072-6694/15/17/4246 |
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