Insulin-like growth factor 1 receptor is a potential therapeutic target for gastrointestinal stromal tumors.
A subset of gastrointestinal stromal tumors (GISTs) lack gain-of-function mutations in c-KIT and PDGFRalpha. 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 IGF1R 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 IGF1R amplification was detected at a significantly higher frequency in WT GISTs, including a pediatric WT GIST, compared with mutant GISTs (P = 0.0173 and P = 0.0163, respectively). Inhibition of IGF1R activity in vitro 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 IGF1R 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.
Departments of Medical Oncology and Pathology and Human Genetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Chi
C
Tarn
Lori
L
Rink
Erin
E
Merkel
Douglas
D
Flieder
Harsh
H
Pathak
Daphne
D
Koumbi
Joseph R
JR
Testa
Burton
B
Eisenberg
Margaret
M
von Mehren
Andrew K
AK
Godwin
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004252:DNA Mutational Analysis; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D000068877:Imatinib Mesylate; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D015398:Signal Transduction
D000970:Antineoplastic Agents; D001549:Benzamides; C501177:NVP-AEW541; D010879:Piperazines; D011743:Pyrimidines; D011758:Pyrroles; D034741:RNA, Small Interfering; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D017526:Receptor, IGF Type 1; D020796:Receptor, Platelet-Derived Growth Factor alpha; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases