Compensatory insulin receptor (IR) activation on inhibition of insulin-like growth factor-1 receptor (IGF-1R): rationale for cotargeting IGF-1R and IR in cancer.

Abstract

Insulin-like growth factor-1 receptor (IGF-1R) is a receptor tyrosine kinase (RTK) and critical activator of the phosphatidylinositol 3-kinase-AKT pathway. IGF-1R is required for oncogenic transformation and tumorigenesis. These observations have spurred anticancer drug discovery and development efforts for both biological and small-molecule IGF-1R inhibitors. The ability for one RTK to compensate for another to maintain tumor cell viability is emerging as a common resistance mechanism to antitumor agents targeting individual RTKs. As IGF-1R is structurally and functionally related to the insulin receptor (IR), we asked whether IR is tumorigenic and whether IR-AKT signaling contributes to resistance to IGF-1R inhibition. Both IGF-1R and IR(A) are tumorigenic in a mouse mammary tumor model. In human tumor cells coexpressing IGF-1R and IR, bidirectional cross talk was observed following either knockdown of IR expression or treatment with a selective anti-IGF-1R antibody, MAB391. MAB391 treatment resulted in a compensatory increase in phospho-IR, which was associated with resistance to inhibition of IRS1 and AKT. In contrast, treatment with OSI-906, a small-molecule dual inhibitor of IGF-1R/IR, resulted in enhanced reduction in phospho-IRS1/phospho-AKT relative to MAB391. Insulin or IGF-2 activated the IR-AKT pathway and decreased sensitivity to MAB391 but not to OSI-906. In tumor cells with an autocrine IGF-2 loop, both OSI-906 and an anti-IGF-2 antibody reduced phospho-IR/phospho-AKT, whereas MAB391 was ineffective. Finally, OSI-906 showed superior efficacy compared with MAB391 in human tumor xenograft models in which both IGF-1R and IR were phosphorylated. Collectively, these data indicate that cotargeting IGF-1R and IR may provide superior antitumor efficacy compared with targeting IGF-1R alone.

• Authors: Elizabeth Buck, Prafulla C Gokhale, Susan Koujak, Eric Brown, Alexandra Eyzaguirre, Nianjun Tao, Maryland Rosenfeld-Franklin, Lorena Lerner, M Isabel Chiu, Robert Wild, David Epstein, Jonathan A Pachter, Mark R Miglarese
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 9 Issue 10 Pg. 2652-64 (Oct 2010) ISSN: 1538-8514 [Electronic] United States
• PMID: 20924128 (Publication Type: Journal Article)

Chemical References

• 3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol
• Imidazoles
• Pyrazines
• Receptor, IGF Type 1
• Receptor, Insulin

Topics

• Animals
• Blotting, Western
• Cell Line, Tumor
• Imidazoles (pharmacology)
• Mammary Neoplasms, Experimental (drug therapy)
• Mice
• Phosphorylation
• Polymerase Chain Reaction
• Pyrazines (pharmacology)
• Receptor, IGF Type 1 (antagonists & inhibitors, metabolism)
• Receptor, Insulin (antagonists & inhibitors, metabolism)
• Signal Transduction