The activated targets of mtor signaling pathway are characteristic for PDGFRA mutant and wild-type rather than KIT mutant GISTs

Z. Sápi, T. Füle, Melinda Hajdu, A. Matolcsy, Linda Moskovszky, Ágnes Márk, A. Sebestyén, G. Bodoky

Research output: Article

16 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)22-33
Number of pages12
JournalDiagnostic Molecular Pathology
Volume20
Issue number1
DOIs
Publication statusPublished - márc. 2011

Fingerprint

Gastrointestinal Stromal Tumors
Sirolimus
Mutation
Phosphotransferases
DNA Sequence Analysis
Exons
TOR Serine-Threonine Kinases
S 6
Platelet-Derived Growth Factor Receptors
Cell Culture Techniques
Immunohistochemistry
Survival
Antibodies

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Cell Biology
  • Molecular Biology

Cite this

@article{94875c93ab5347aa8d1f02685fd2187f,
title = "The activated targets of mtor signaling pathway are characteristic for PDGFRA mutant and wild-type rather than KIT mutant GISTs",
abstract = "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.",
keywords = "GIST, mTOR signaling pathway, PDGFRA",
author = "Z. S{\'a}pi and T. F{\"u}le and Melinda Hajdu and A. Matolcsy and Linda Moskovszky and {\'A}gnes M{\'a}rk and A. Sebesty{\'e}n and G. Bodoky",
year = "2011",
month = "3",
doi = "10.1097/PDM.0b013e3181eb931b",
language = "English",
volume = "20",
pages = "22--33",
journal = "Diagnostic Molecular Pathology",
issn = "1052-9551",
publisher = "Lippincott Williams and Wilkins",
number = "1",

}

TY - JOUR

T1 - The activated targets of mtor signaling pathway are characteristic for PDGFRA mutant and wild-type rather than KIT mutant GISTs

AU - Sápi, Z.

AU - Füle, T.

AU - Hajdu, Melinda

AU - Matolcsy, A.

AU - Moskovszky, Linda

AU - Márk, Ágnes

AU - Sebestyén, A.

AU - Bodoky, G.

PY - 2011/3

Y1 - 2011/3

N2 - 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.

AB - 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.

KW - GIST

KW - mTOR signaling pathway

KW - PDGFRA

UR - http://www.scopus.com/inward/record.url?scp=79952182082&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79952182082&partnerID=8YFLogxK

U2 - 10.1097/PDM.0b013e3181eb931b

DO - 10.1097/PDM.0b013e3181eb931b

M3 - Article

C2 - 21326036

AN - SCOPUS:79952182082

VL - 20

SP - 22

EP - 33

JO - Diagnostic Molecular Pathology

JF - Diagnostic Molecular Pathology

SN - 1052-9551

IS - 1

ER -