TRKing down drug resistance in NTRK fusion‐positive cancers

In a recent issue of The Journal of Pathology, Chen and colleagues established novel patient‐derived ex vivo models of NTRK fusion‐positive soft tissue sarcoma to characterize resistance mechanisms against targeted therapy with tyrosine kinase inhibitors. Prolonged exposure to escalating concentrati...

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Bibliographic Details
Published in:The Journal of pathology 2024-10, Vol.264 (2), p.129-131
Main Authors: Parrish, Abigail G, Szulzewsky, Frank
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
AKT protein
Drug resistance
Neurofibromin 2
NF2
patient‐derived ex vivo cell model
Raf protein
Soft tissue sarcoma
therapy resistance
TOR protein
tyrosine kinase inhibitor
Tyrosine kinase inhibitors
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Summary:In a recent issue of The Journal of Pathology, Chen and colleagues established novel patient‐derived ex vivo models of NTRK fusion‐positive soft tissue sarcoma to characterize resistance mechanisms against targeted therapy with tyrosine kinase inhibitors. Prolonged exposure to escalating concentrations of the tyrosine kinase inhibitor, entrectinib, ultimately led to the occurrence of resistant clones that harbored an inactivating mutation in the NF2 gene, not previously described in this context, accompanied by increased PI3K/AKT/mTOR and Ras/Raf/MEK/ERK signaling. Finally, an inhibitor screen identified, among others, MEK and mTOR inhibitors as potential combination agents. © 2024 The Pathological Society of Great Britain and Ireland.
ISSN:0022-3417
1096-9896
1096-9896
DOI:10.1002/path.6341