Molecular Cancer apeutics apeutic Discovery pensatory Insulin Receptor ( IR ) Activation on Inhibition of lin-Like Growth Factor-1 Receptor ( IGF-1 R ) : Rationale Ther Cotargeting IGF-1 R and IR in Cancer

Downloa lin-like growth factor-1 receptor (IGF-1R) is a receptor tyrosine kinase (RTK) and critical activator of osphatidylinositol 3-kinase–AKT pathway. IGF-1R is required for oncogenic transformation and tumoris. These observations have spurred anticancer drug discovery and development efforts for both biol and small-molecule IGF-1R inhibitors. The ability for one RTK to compensate for another to maintain cell viability is emerging as a common resistance mechanism to antitumor agents targeting individual As IGF-1R is structurally and functionally related to the insulin receptor (IR), we asked whether IR is igenic and whether IR-AKT signaling contributes to resistance to IGF-1R inhibition. Both IGF-1R and are tumorigenic in a mouse mammary tumor model. In human tumor cells coexpressing IGF-1R and irectional cross talk was observed following either knockdown of IR expression or treatment with a ve anti–IGF-1R antibody, MAB391. MAB391 treatment resulted in a compensatory increase in phosphoich was associated with resistance to inhibition of IRS1 and AKT. In contrast, treatment with OSI-906, a molecule dual inhibitor of IGF-1R/IR, resulted in enhanced reduction in phospho-IRS1/phospho-AKT e to MAB391. Insulin or IGF-2 activated the IR-AKT pathway and decreased sensitivity to MAB391 but OSI-906. In tumor cells with an autocrine IGF-2 loop, both OSI-906 and an anti–IGF-2 antibody reduced ho-IR/phospho-AKT, whereas MAB391 was ineffective. Finally, OSI-906 showed superior efficacy comwith MAB391 in human tumor xenograft models in which both IGF-1R and IR were phosphorylated. pared Collectively, these data indicate that cotargeting IGF-1R and IR may provide superior antitumor efficacy compared with targeting IGF-1R alone. Mol Cancer Ther; 9(10); 2652–64. ©2010 AACR.