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The Activated Targets of mTOR Signaling Pathway Are Characteristic for PDGFRA Mutant and Wild-type Rather Than KIT Mutant GISTs

Sápi, Zoltán MD, PhD; Füle, Tibor PhD; Hajdu, Melinda MD, PhD; Matolcsy, András MD, DSc; Moskovszky, Linda MD; Márk, Ágnes PhD; Sebestyén, Anna PhD; Bodoky, György MD, DSc

Diagnostic Molecular Pathology: March 2011 - Volume 20 - Issue 1 - p 22–33
doi: 10.1097/PDM.0b013e3181eb931b
Original Articles
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The therapy for gastrointestinal stromal tumors (GISTs) has been revolutionized by tyrosin kinase inhibitors. Clinicopathologic studies have been conducted to assess therapeutical responses in cases with KIT and platelet-derived growth factor receptor α (PDGFRA) gene mutations. Cell culture data suggest that Akt/mammalian target of rapamycin (mTOR) kinase signaling may be important in GIST. The aim of our study was to determine the activity of the mTOR pathway in a larger series of GISTs (108 different cases) with different exon mutation types. The KIT and/or PDGFRA mutation status of 108 GIST patients was analyzed by direct DNA sequencing. Immunohistochemistry was performed on tissue microarrays using antibodies for phospho-p70S6 kinase, phospho-4EBP1, and phospho-S6, which are downstream target proteins of mTOR. DNA sequencing identified 73 cases with mutations of KIT and 12 cases with PDGFRA mutations. Wild-type receptors were present in 23 cases. KIT exon mutations were accompanied by the activation of the mTOR pathway in 28 of 73 (38.4%) cases, whereas PDGFRA mutant GISTs showed activation in 10 of 12 (83.3%) cases. Wild-type cases were accompanied by mTOR activation in 17 of 23 (73.9%) cases. Our results indicate that the activation of the mTOR pathway is not a general hallmark of GIST with KIT mutations. However, mTOR signaling seems to be activated in PDGFRA mutants and in wild-type cases, which suggests that mTOR or upstream mTOR inhibitors may be therapeutically useful in primary resistant GISTs and confirms earlier data that mTOR is a crucial survival pathway in resistant GISTs.

*1st Department of Pathology and Experimental Cancer Research, Semmelweis University

Department of Oncology, Szent László Hospital, Budapest, Hungary

A part of this study was financially supported by Novartis Ltd., Hungarian division.

Reprints: Zoltán Sápi, MD, PhD, 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, Üllői út 26, Hungary (e-mail: zsapi@freemail.hu).

© 2011 by Lippincott Williams & Wilkins.