We have located links that may give you full text access.
New Mechanisms of mTOR Pathway Activation in KIT-mutant Malignant GISTs.
A great majority of gastrointestinal stromal tumors (GISTs) are primarily driven by gain-of-function KIT receptor tyrosine kinase mutations that subsequently lead to activation of phosphatidiylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway, a downstream effector of KIT signaling. KIT tyrosine kinase inhibitor, imatinib mesylate, has been successfully used for the treatment of primary, advanced, and disseminated GISTs. Recently, activation of mTOR pathway independent of KIT signaling was demonstrated in imatinib mesylate naïve malignant GISTs and treatment-resistant metastatic tumors. This activation was attributed to oncogenic mutations in PIK3CA encoding PI3K 110α subunit, or to the inactivation of PTEN tumor suppressor, a potent mTOR negative regulator. In this study, mTOR pathway genes were evaluated in 14 imatinib mesylate naïve, KIT-mutant, malignant small intestinal GISTs using next-generation sequencing. Mutations were detected in 3 (21%) of 14 analyzed tumors: (1) c.3200A>T substitution in PIK3CB encoding PI3K 110β subunit, (2) c.1040A>G substitution in tuberous sclerosis complex (TSC2) encoding tuberin, mTOR down-regulator (3) c.6625C>G substitution in mTOR. At the protein level, these changes were predicted to cause, respectively, PIK3CB p.D1067V, TSC2 p.K347R, and mTOR p.L2209V mutations. Previously reported "in vitro" experiments with mouse 3T3 fibroblasts demonstrated oncogenic potential of PIK3CB p.D1067V and mTOR p.L2209V mutants; whereas, PolyPhen-2 software analysis predicted TSC2 p.K347R mutation to likely have a damaging impact on tuberin function. The results of this and previous studies indicate diversity of genetic changes leading to activation of PI3K-AKT-TSC-mTOR pathway in malignant GISTs. Extensive genotyping of the genes involved in mTOR pathway demonstrates common alterations that need to be considered in targeted treatment.
Full text links
Related Resources
Trending Papers
Proximal versus distal diuretics in congestive heart failure.Nephrology, Dialysis, Transplantation 2024 Februrary 30
World Health Organization and International Consensus Classification of eosinophilic disorders: 2024 update on diagnosis, risk stratification, and management.American Journal of Hematology 2024 March 30
Heart failure with preserved ejection fraction: diagnosis, risk assessment, and treatment.Clinical Research in Cardiology : Official Journal of the German Cardiac Society 2024 April 12
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app
All material on this website is protected by copyright, Copyright © 1994-2024 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.
By using this service, you agree to our terms of use and privacy policy.
Your Privacy Choices
You can now claim free CME credits for this literature searchClaim now
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app