Insulin-like growth factor 1 receptor (IGF-1R): A potential therapeutic target for gastrointestinal stromal tumors (GIST)

Abstract

10507 Background: Most GISTs possess a gain-of-function mutation in c-KIT or PDGFRα, which are targets of imatinib mesylate. However, wild type (WT) GIST and pediatric GIST lack mutations in either gene. These GISTs tend to be less responsive to imatinib-based therapies and have a poor prognosis. Overexpression of IGF-1R has been identified in many tumor types and inhibitors are currently being studied clinically. We identified amplification of IGF1R in a SNP analysis of GIST tumors and thus studied its potential as a therapeutic target in WT and mutant GIST. Methods: Expression of IGF-1R and downstream effectors in clinical GIST samples were examined using immunoblots and immunohistochemistry. Copy number changes of the IGF1R gene were examined by genomic qPCR and FISH. The role of IGF-1R in GIST signaling and viability were analyzed using NVP-AEW541 (Novartis, Basel, Switzerland), a specific inhibitor of IGF-1R, alone and in combination with imatinib, or via siRNA silencing of IGF1R. Results: IGF-1R was dramatically overexpressed and IGF1R amplification was detected at a significantly higher frequency in majority of WT GISTs and pediatric GIST when compared with mutant GISTs (P=0.000002 and P=0.0163, respectively). Inhibition of IGF-1R activity with NVP- AEW541 or down regulation of expression using siIGF1R led to cytotoxicity and induced apoptosis in both imatinib sensitive and resistant GIST cells via AKT and MAPK signaling. Combination of NVP-AEW541 and imatinib in GIST cell lines induced a strong cytotoxicity response. Conclusions: Our results reveal for the first time that the IGF1R gene is amplified and the protein is overexpressed in WT and pediatric GISTs. Our results demonstrate that the aberrant expression of IGF-1R may be associated with oncogenesis in a subset of GISTs that lack c-KIT or PDGFRα mutations and suggest an alternative or complementary therapeutic regimen in the clinical management of GIST, especially in tumors that respond less favorably to imatinib-based therapy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis, Pfizer, MedImmune, Human Genome Sciences, Johnson & Johnson, Transgenomic Inc. MolecularMD Novartis, Pfizer Novartis, Pfizer