Insulin-like growth factor 1 receptor is a potential therapeutic target for gastrointestinal stromal tumors

Abstract

A subset of gastrointestinal stromal tumors (GISTs) lack gain-offunction mutations in c-KIT and PDGFR␣. 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.pediatric GIST ͉ tyrosine kinase inhibitors ͉ imatinib mesylase ͉ adult wild-type GIST ͉ NYP-AEW541

Imatinib plus low‐dose doxorubicin in patients with advanced gastrointestinal stromal tumors refractory to high‐dose imatinib

“…26 Amplification of the IGF1R gene has been observed recently in this subset of patients, 27 but acquired mutations were not seen at progressive disease, suggesting different mechanisms of acquired resistance than in patients with KIT exon 11 mutations. 28 We observed, in accordance with the literature 4,29 that first-line therapy with 400 mg imatinib resulted in shorter PFS in WT-KIT patients than in patients with KIT exon 11 mutations.…”

A molecular portrait of gastrointestinal stromal tumors: an integrative analysis of gene expression profiling and high-resolution genomic copy number

“…29 Similarly, previous studies have suggested that both adult and pediatric WT GISTs may share alterations in IGF-1 pathway. [30][31][32][33] By merging copy number and gene expression data, we observed a high level of correlation between CNAs and the correspondent gene expression profile. This was especially true on chromosome 14, in the q23.1-qter region, which harbors several possible target genes (DAAM1, RTN1, PPM1A, DACT1, MPP5, SNW1, FOXN3, PPM1A and PTPN21).…”

Succinate dehydrogenase-deficient GISTs are characterized by IGF1R overexpression

“…It has been consistently demonstrated that insulin-like growth factor 1 receptor protein (IGF1R) is highly overexpressed in certain subsets of GISTs, which are generally described as being either 'pediatric' or 'wild type' or both. [10][11][12][13] We hypothesized that IGF1R overexpression would be a defining feature of SDH-deficient GISTs as a group, rather than being limited to pediatric GISTs or being a feature of all wild-type GISTs or all pediatric GISTs. Therefore, IGF1R inhibition may be a rational therapeutic approach for the 5À7.5% of all gastric GISTs that are SDH deficient.…”