Abstract 1631: Tumorigenicity of IGF-1R and IR: Rationale for co-targeting IGF-1R and IR in cancer
Authors: Lorena Lerner, Qing Liu, Nianjun Tao, John Yang, Eric Brown, Susan Koujak, Brian Krieger, Lu Huang, Maryland Rosenfeld-Franklin, Mark Miglarese, Jonathan Pachter, Murray O. Robinson, M. Isabel Chiu, David Epstein, Elizabeth Buck
Journal: Cancer Research (2011)

Abstract The Type 1 insulin-like growth factor receptor (IGF-1R) is a well established mediator of tumor cell proliferation and survival. IGF-1R is required for cellular transformation by a number of oncogenes including Ras, and expression of IGF-1R can promote tumor formation in vivo. Blockade of IGF-1R signaling by either genetic or pharmacological methods results in inhibition of tumor cell proliferation. This understanding has spurred the evaluation of a number of IGF-1R inhibitors in the clinic, including both neutralizing antibodies and small molecule kinase inhibitors. IGF-1R is structurally and functionally related to the insulin receptor (IR). Although IR is appreciated for its classical role in glucose metabolism, IR can also regulate cellular proliferation. Furthermore, there is evidence for compensatory crosstalk between IGF-1R and IR. In embryonic development IR signaling can compensate for loss of IGF-1R to maintain normal embryonic weight. A growing body of data indicates that tumor cells may also exploit IR signaling for proliferation and survival. Tumor cells frequently co-express both IGF-1R and IR, and increased expression of both IGF ligands and insulin are associated with increased risk of cancer. Elevated expression of the IR(A) fetal variant, which is potently activated by both insulin and IGF-2, is observed in select human tumors. Although the tumorigenicity for IGF-1R is well described, the potential for IR as a tumor maintenance gene in vivo has thus far not been established. Herein, we sought to address the tumorigenic potential for IGF-1R compared with IR(A). We used a mouse mammary tumor model driven by an inducible human HER2 oncogene under doxycyclin-directed expression, where repression of HER2 expression upon doxycyclin withdrawal was followed by introduction of genes encoding either IGF-1R or IR(A) in combination with IGF2. We find that either IGF-1R or IR(A), in combination with the ligand IGF2, can complement tumor growth. The growth of both IGF-1R and IR(A) direct complementation (DC) tumor models could be inhibited by the dual IGF-1R/IR small molecule inhibitor OSI-906. Cell lines derived from the IGF-1R and IR(A) DC tumors show that expression of either receptor individually can maintain signaling through the IRS-AKT signaling pathway. Collectively, these observations show that either IGF-1R or IR(A) have tumorigenic potential, and indicate that dual targeting of IGF-1R and IR may be required for optimal activity in tumors where both receptors are present and activated. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1631. doi:10.1158/1538-7445.AM2011-1631