Abstract 5633: Co-targeting the IGF1R pathway and compensatory signaling enhances cytotoxicity in head and neck cancer.

Abstract

Abstract The 5-year survival rate for patients with cancer of the Head and Neck (HNC) has not significantly improved over the past decade. Clearly, new therapeutic targets and strategies for employing existing targeted and cytotoxic therapies are needed. Studies have shown both expression and phosphorylation of the insulin-like growth factor 1 receptor (IGF1R) in both head and neck cancer cell lines and patient tumor samples. We found that small molecule inhibitors targeting IGF1R, when used as a single agent, caused varying degrees of cytotoxicity in HNC cell lines. In order to determine whether the variable biological response to IGF1R inhibition was caused by differences in the effects of the IGF1R inhibitors on the cell signaling networks of the HNC cell lines, we performed reverse phase proteomic array analysis on a panel of HNC cell lines treated with IGF1R inhibitors. Preliminary results suggest that treatment with IGF1R inhibitors caused increased expression and/or phosphorylation of a number of proteins in the array. We hypothesize that these alterations represent compensatory signaling pathways that provide resistance to cytotoxicity upon treatment with IGF1R inhibitors. In order to identify possible mechanisms of compensation for the loss of IGF1R pathway signaling, we screened a panel of small molecule inhibitors of the IGF1R/PI3K/AKT signaling pathway against a panel of inhibitors of proteins important in HNC cell signaling Preliminary results indicate that the inhibition of epigenetic modifying proteins as well as members of canonical cell signaling pathways in combination with inhibition of IGF1R signaling leads to a synergistic increase in cytotoxicity. This suggests that compensatory mechanisms exist in HNC that serve to blunt the cytotoxic effect of inhibition of IGF1R. Co-targeting IGF1R and members of these compensatory pathways may be a viable therapeutic strategy. Citation Format: Mark J. Axelrod, Daniel Gioeli, Elizabeth R. Sharlow, Mark C. Conaway, Rolando E. Mendez, Ashraf Khalil, Linnea Taniguchi, Emmanual F. Petricoin, Stephanie Leimgruber, Michael J. Weber, Mark J. Jameson. Co-targeting the IGF1R pathway and compensatory signaling enhances cytotoxicity in head and neck cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5633. doi:10.1158/1538-7445.AM2013-5633