Discovery of oncogenic ROS1 missense mutations with sensitivity to tyrosine kinase inhibitors
Abstract: ROS1 is the largest receptor tyrosine kinase in the human genome. Rearrangements of the ROS1 gene result in oncogenic ROS1 kinase fusion proteins that are currently the only validated biomarkers for targeted therapy with ROS1 TKIs in patients. While numerous somatic missense mutations in ROS1 exist in the cancer genome, their impact on catalytic activity and pathogenic potential is unknown. We interrogated the AACR Genie database and identified 34 missense mutations in the ROS1 tyrosine kinase domain for further analysis. Our experiments revealed that these mutations have varying effects on ROS1 kinase function, ranging from complete loss to significantly increased catalytic activity. Notably, Asn and Gly substitutions at Asp2113 in the ROS1 kinase domain were found to be TKI‐sensitive oncogenic variants in cell‐based model systems. In vivo experiments showed that ROS1 D2113N induced tumor formation that was sensitive to crizotinib and lorlatinib, FDA‐approved ROS1‐TKIs. Collectively, these findings highlight the tumorigenic potential of specific point mutations within the ROS1 kinase domain and their potential as therapeutic targets with FDA‐approved ROS1‐TKIs.
- Location
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Deutsche Nationalbibliothek Frankfurt am Main
- Extent
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Online-Ressource
- Language
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Englisch
- Bibliographic citation
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Discovery of oncogenic ROS1 missense mutations with sensitivity to tyrosine kinase inhibitors ; day:17 ; month:08 ; year:2023 ; extent:27
EMBO molecular medicine / European Molecular Biology Organization ; (17.08.2023) (gesamt 27)
- Creator
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Iyer, Sudarshan R.
Nusser, Kevin
Jones, Kristen
Shinde, Pushkar
Keddy, Clare
Beach, Catherine Z.
Aguero, Erin
Force, Jeremy
Shinde, Ujwal
Davare, Monika A.
- DOI
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10.15252/emmm.202217367
- URN
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urn:nbn:de:101:1-2023081715285421768411
- Rights
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Last update
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14.08.2025, 10:49 AM CEST
Data provider
Deutsche Nationalbibliothek. If you have any questions about the object, please contact the data provider.
Associated
- Iyer, Sudarshan R.
- Nusser, Kevin
- Jones, Kristen
- Shinde, Pushkar
- Keddy, Clare
- Beach, Catherine Z.
- Aguero, Erin
- Force, Jeremy
- Shinde, Ujwal
- Davare, Monika A.
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