Discovery of oncogenic ROS1 missense mutations with sensitivity to tyrosine kinase inhibitors

Autor: Sudarshan R Iyer, Kevin Nusser, Kristen Jones, Pushkar Shinde, Clare Keddy, Catherine Z Beach, Erin Aguero, Jeremy Force, Ujwal Shinde, Monika A Davare
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: EMBO Molecular Medicine, Vol 15, Iss 10, Pp n/a-n/a (2023)
Druh dokumentu: article
ISSN: 1757-4684
1757-4676
DOI: 10.15252/emmm.202217367
Popis: 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.
Databáze: Directory of Open Access Journals
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