Molecular mechanisms of secondary imatinib resistance in patients with gastrointestinal stromal tumors

Wang, Chun Meng; Huang, Kerson; Zhou, Ye; Du, Changqing; Ye, Yan Wei; Fu, Hong; Zhou, Xiao Yan; Shi, Ying

doi:10.1007/s00432-009-0753-7

Cited by 33 publications

(35 citation statements)

References 27 publications

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“…The results showed that the activation of the downstream AKT/ mTOR might be more important in imatinib secondary resistance mechanism than PI3K. This may be a coincidence in part with the previously reported data [8]. The most direct evidence from 20 pairs of GIST samples before and after imatinib treatment showed that AKT/mTOR was activated in half of GISTs after secondary resistance to imatinib developed, but this phenomenon was not observed in the GISTs sensitive to imatinib, even if the patients also received imatinib treatment for some time.…”

Section: Discussionsupporting

confidence: 64%

“…Strong KIT phosphorylation and evidence of activated downstream signaling pathways, including the MAP kinase pathway (RAF, MEK, ERK), the STAT pathway and the PI3K/AKT/mTOR pathway have been reported [7][8][9][13][14][15]. Results from GIST cell line data have shown that the PI3-K/AKT pathway might be more relevant than MEK/ MAPK for therapeutic targeting in imatinib-resistant GISTs [9].…”

Section: Discussionmentioning

confidence: 97%

“…Recent studies have indicated that PI3K/ AKT/mTOR pathway activation may be related to imatinib resistance [7][8][9], but no one has reported the crucial signal change in this pathway before and after imatinib treatment in the same patient group to analyze the relationship between the activation of this pathway and the imatinib secondary resistance mechanism.…”

Section: Introductionmentioning

confidence: 98%

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PI3K/AKT/mTOR pathway is activated after imatinib secondary resistance in gastrointestinal stromal tumors (GISTs)

Dang

Gao

et al. 2015

Med Oncol

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Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of the rapamycin (mTOR) pathway activation may be related to imatinib resistance; however, no study has focused on whether signal conduction of this pathway will change after imatinib resistance. A total of 111 GIST samples from 91 patients were used in this study, including 20 pairs of samples before and after imatinib treatment. Immunohistochemistry was performed on tissue for p-KIT (phospho-KIT), PTEN (phosphatase and tensin homolog deleted on chromosome ten), PI3K, phospho-AKT (p-AKT), phospho-4EBP1 (p-4EBP1) and phospho-S6 (p-S6RP). The activation of AKT/mTOR was significantly higher in imatinib secondary resistant GIST (53.1 %) than in imatinib-sensitive (27.1 %) and primary resistant GIST (33.3 %) (P = 0.049). In the analysis of 20 pairs of samples, comparing pre-imatinib GIST with on-treatment ones, the PI3K status was changed from inactivated to activated in four cases each in eight patients with effective imatinib and 12 patients whose secondary resistance happened, respectively. AKT/mTOR status was inactivated in pre-imatinib and on-treatment samples in eight patients with effective imatinib; however, the status of six patients was changed from inactivated to activated in 12 patients at the time of tumor progression. The negative expression of p-KIT was accompanied with PI3K pathway and/or AKT/mTOR pathway activity in some GISTs with secondary resistance. PI3K/AKT/mTOR pathway can be partly activated after imatinib secondary resistance in GIST. In this pathway, activation of AKT/mTOR is a more crucial factor, and PI3K activation may be the early part of secondary resistance.

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Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 98%

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PI3K/AKT/mTOR pathway is activated after imatinib secondary resistance in gastrointestinal stromal tumors (GISTs)

Dang

Gao

et al. 2015

Med Oncol

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“…Finally, to explain the possible relationship of leptin and NGAL levels with imatinib therapy, we have to bear in mind that imatinib modulates several signal pathways such as Kit, PDGFRs, MEK/MAPK and others [28,29,30,31], while NGAL and leptin regulate these pathways, and their expression could be regulated by the same pathways [32,33,34,35]. …”

Section: Discussionmentioning

confidence: 99%

Imatinib Mesylate Therapy Induces Reduction in Neutrophil Gelatinase-Associated Lipocalin Serum Levels and Increase in Leptin Concentrations in Chronic Myeloid Leukemia Patients in Molecular Remission

Alonci

Allegra²,

Russo³

et al. 2011

Acta Haematol

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The aim of the present study was to determine serum levels of neutrophil gelatinase-associated lipocalin (NGAL) and leptin in patients with chronic myeloid leukemia (CML) at diagnosis and after imatinib therapy when patients achieved a complete molecular remission. The study was conducted on 22 patients with CML in the chronic phase and 10 healthy subjects. The median serum NGAL levels in CML patients at diagnosis were significantly higher compared to age-matched controls. After imatinib therapy, all patients achieved complete molecular remission and NGAL levels decreased and were found significantly lower with respect to the baseline. No significant correlations were found between NGAL levels and other disease parameters. Before imatinib therapy, the median blood leptin levels were not significantly different from those of controls. After therapy with imatinib, all patients in molecular remission presented an increase in leptin levels. Future research is eagerly awaited as it may demonstrate the real role of NGAL and leptin in the onset and progression of CML.

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“…Activation of KIT or platelet-derived growth factor receptor alpha (PDGFRA) gene mutation is a major force in GISTs. As reported, 95% of GISTs express KIT, and more than 80% have gain of function mutations of KIT or PDGFRA [3]. Abdominal pain and gastrointestinal bleeding were the more common symptoms [4].…”

Section: Introductionmentioning

confidence: 80%

Gastrointestinal Stromal Tumors Short Review on KIT/PDGFRA Gene Mutations and Molecular Therapy

Xie¹

2013

J Gastrointest Dig Syst

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Gastrointestinal stromal tumors (GISTs) are most frequent mesenchimal neoplasms of the gastrointestinal tract. Current knowledge demonstrates that the KIT and PDGFRA gene mutations play a central part in the pathogenesis. Mutations can be subdivided into primary and secondary mutations. Secondary mutations usually occur in KIT kinase domains after tyrosine kinase inhibitors treatment resulting in resistance to drugs. Besides surgery, therapy with tyrosine kinase inhibitors has led to develop novel treatments for patients now. However, secondary resistance has become a significant concern, illustrating the need to increase collaboration between surgical management and molecular therapy.

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Molecular mechanisms of secondary imatinib resistance in patients with gastrointestinal stromal tumors

Abstract: Novel additional mutations of KIT gene exon 13 or exon 17 indicate the likely mechanism of secondary resistance to imatinib. The PI3-K/AKT pathway might be more relevant than MEK/MAPK for therapeutic targeting in imatinib-resistant GIST patients with secondary mutation.

Cited by 33 publications

References 27 publications

PI3K/AKT/mTOR pathway is activated after imatinib secondary resistance in gastrointestinal stromal tumors (GISTs)

PI3K/AKT/mTOR pathway is activated after imatinib secondary resistance in gastrointestinal stromal tumors (GISTs)

Imatinib Mesylate Therapy Induces Reduction in Neutrophil Gelatinase-Associated Lipocalin Serum Levels and Increase in Leptin Concentrations in Chronic Myeloid Leukemia Patients in Molecular Remission

Gastrointestinal Stromal Tumors Short Review on KIT/PDGFRA Gene Mutations and Molecular Therapy

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