Insulin-like growth factor 1 receptor is a potential therapeutic target for gastrointestinal stromal tumors
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- Chi Tarn
- Departments of *Medical Oncology and
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- Lori Rink
- Departments of *Medical Oncology and
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- Erin Merkel
- Departments of *Medical Oncology and
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- Douglas Flieder
- Pathology and
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- Harsh Pathak
- Departments of *Medical Oncology and
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- Daphne Koumbi
- Human Genetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111; and
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- Joseph R. Testa
- Human Genetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111; and
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- Burton Eisenberg
- Norris Cotton Cancer Center, Dartmouth–Hitchcock Medical Center, Lebanon, NH 03756
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- Margaret von Mehren
- Departments of *Medical Oncology and
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- Andrew K. Godwin
- Departments of *Medical Oncology and
抄録
<jats:p> A subset of gastrointestinal stromal tumors (GISTs) lack gain-of-function mutations in c- <jats:italic>KIT</jats:italic> and <jats:italic>PDGFR</jats:italic> α. These so-called wild-type (WT) GISTs tend to be less responsive to imatinib-based therapies and have a poor prognosis. We identified amplification of <jats:italic>IGF1R</jats:italic> in a SNP analysis of GIST and thus studied its potential as a therapeutic target in WT and mutant GIST. Expression of IGF1R and downstream effectors in clinical GIST samples was examined by using immunoblots and immunohistochemistry. The roles of IGF1R signaling in GIST and viability were analyzed by using NVP-AEW541, an inhibitor of IGF1R, alone and in combination with imatinib, or via siRNA silencing of IGF1R. IGF1R was strongly overexpressed, and <jats:italic>IGF1R</jats:italic> amplification was detected at a significantly higher frequency in WT GISTs, including a pediatric WT GIST, compared with mutant GISTs ( <jats:italic>P</jats:italic> = 0.0173 and <jats:italic>P</jats:italic> = 0.0163, respectively). Inhibition of IGF1R activity <jats:italic>in vitro</jats:italic> with NVP-AEW541 or down-regulation of expression with siIGF1R led to cytotoxicity and induced apoptosis in GIST cell lines via AKT and MAPK signaling. Combination of NVP-AEW541 and imatinib in GIST cell lines induced a strong cytotoxicity response. Our results reveal that <jats:italic>IGF1R</jats:italic> is amplified and the protein is overexpressed in WT and pediatric GISTs. We also demonstrate that the aberrant expression of IGF1R may be associated with oncogenesis in WT GISTs and suggest an alternative and/or complementary therapeutic regimen in the clinical management of all GISTs, especially in a subset of tumors that respond less favorably to imatinib-based therapy. </jats:p>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 105 (24), 8387-8392, 2008-06-17
Proceedings of the National Academy of Sciences