The insulin-like growth factor system as a potential therapeutic target in gastrointestinal stromal tumors

Abstract

The majority of gastrointestinal stromal tumors (GISTs) are characterized by oncogenic gain-of-function mutations in the receptor tyrosine kinase (RTK) c-KIT with a minority in PDGFRalpha. Therapy for GISTs has been revolutionized by the use of the selective tyrosine kinase inhibitor imatinib mesylate (IM). For the subset (approximately 10-15%) of GISTs that lack oncogenic mutations in these receptors, the genetic changes driving tumorigenesis are unknown. We recently reported that the gene encoding the insulin-like growth factor 1 receptor (IGF-1R) is amplified in a subset of GISTs, and the IGF-1R protein is overexpressed in wild-type and pediatric GISTs. In this report we present a more complete picture of the involvement of components of the insulin-like growth factor-signaling pathway in the pathogenesis of GISTs. We also discuss how the IGF pathway may provide additional molecular targets for the treatment of GISTs that respond poorly to IM therapy.

Figure 1. The insulin-like growth factor system and its potential role in tumorigenesis

The IGF system ligands IGF-1, IGF-2, and insulin (Ins) circulate and interact with binding proteins (IGF-BP) or bind to the membrane-bound receptors IGF-1R, IGF-2R, the insulin receptor itself (IR) or hybrid receptors (IGF-1R/IR). Ligand binding results in receptor autophosphorylation and activation of downstream signaling pathways leading to cell proliferation, survival, and metastasis.

Figure 2. IGF-1R expression in GIST biopsies

Immunoblot assays of 27 consecutive fresh-frozen GIST biopsies using an anti-IGF-1R antibody. 100 µg of WCE from each sample was subjected to immunoblotting. c-KIT or PDGFRα genotype for each GIST is listed below (+ or −). Asterisks indicate WT GISTs.

Figure 3. IGF-1 expression in various sarcomas

IHC staining was performed as described in ref. on tissue from a leiomyosarcoma, liposarcoma, WT GIST and mutant GIST. The primary IGF-1 antibody was used at a 1:100 dilution and was purchased from Santa Cruz Biotechnology Inc. Top two panels show positive IGF-1 staining in the leiomyosarcoma and liposarcoma, whereas the two bottom panels show no IGF-1 expression in both GIST samples (WT and mutant). Pictures were taken with 200x magnification.

Figure 4. Expression of IGF components in WT and mutant GISTs by immunohstochemistry (IHC)

IGF-1R, IGF-1, IGF-2 and KIT expression in WT and mutant GISTs as analyzed by IHC. Primary antibodies used include IGF-2 (1:500 dilution, Abcam), IGF-1R (1:50 dilution, Cell Signaling) and KIT (1:2000 dilution, Dako).

Figure 5. Current and future paradigms for treatment of GISTs

A. First line therapy for treatment of GISTs is IM, however, primary and secondary resistance has become a major clinical obstacle. Currently the second line therapy is sunitinib, which shows limited benefits and has led to the movement of additional agents into clinical trials. B. The future paradigm for GIST treatment will most likely include a molecular characterization (i.e. genotypic status, expression profiles) of individual tumors before treatment decision. This type of characterization has the potential to lead to more effective treatment models in the future.