Abstract 1654: Compensatory insulin receptor (IR) activation upon inhibition of insulin-like growth factor receptor (IGF-1R): Rationale for co-targeting IGF-1R and IR in cancer

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC The insulin-like growth factor receptor (IGF-1R) is a receptor tyrosine kinase (RTK) and a critical mediator of signaling through the PI3K-AKT pathway. IGF-1R is required for oncogenic transformation and tumorigenesis, and inhibiton of IGF-1R results in reduced proliferation and survival of tumor cells. These observations have spurred intense drug discovery and development efforts for both biologic and small molecule IGF-1R inhibitors for the treatment of cancer. The ability for one RTK to compensate for another to maintain growth and survival signaling in tumor cells is emerging as a common mechanism of resistance to anti-tumor agents that selectively target individual RTKs. As IGF-1R is structurally and functionally related to the insulin receptor (IR), and IR can also activate tumor cell AKT signaling and cellular transformation, we asked whether IR signaling can contribute to resistance to IGF-1R inhibition in tumor cells. In a panel of human tumor cell lines, IGF-1R/IR crosstalk was observed after treatment with a selective anti-IGF-1R monoclonal antibody, MAB391. Tumor cells treated with MAB391 responded with a compensatory increase in phospho-IR, which was also associated with an inability to fully inhibit phospho-IRS1 and phospho-AKT. In contrast, treatment with OSI-906, a small molecule dual kinase inhibitor of IGF-1R and IR, resulted in enhanced inhibition of the IRS1-AKT signaling pathway. OSI-906 showed superior efficacy compared to MAB391 in human tumor xenograft models where both phospho-IR and phospho-IGF-1R were detectable, and presumably both receptors were required by tumor cells for growth and/or survival. Both insulin and IGF-2 can activate the IR-AKT pathway and we show that treatment with either growth factor resulted in decreased sensitivity of tumor cells to MAB391, but not OSI-906. In tumor cells with an autocrine IGF-2 signaling loop, both OSI-906 and an anti-IGF-2 neutralizing antibody reduced phospho-IR and phospho-AKT levels, whereas MAB391 was ineffective. Collectively, these data indicate that OSI-906, which co-targets IGF-1R and IR, may provide superior efficacy as compared to agents that selectively target only IGF-1R. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1654.