Inhibition of insulin-like growth factor-1 receptor signaling impairs proliferation of head and neck, lung, prostate and breast cancer cells

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The successful application of targeted molecular agents in cancer therapy may ultimately be facilitated by the use of combination strategies. Under this paradigm, multiple proteins involved in maintaining the transformed phenotype are co-targeted to achieve an additive or synergistic anti-cancer effect. The insulin-like growth factor-1 receptor (IGF-1R) is one such target, having been implicated in cellular proliferation, apoptosis, migration and resistance to chemotherapy and radiation. We investigated a panel of tumor cell lines for expression of the IGF-1R, finding universal expression in several lines: head and neck (SCC1, SCC6, SCC1483, SCC22B), prostate (PC3, DU145, LNCAP), breast (MCF7, SKBR3), vulva (A431), glioma (T98G) and lung (H226, A549). Two anti-IGF-1R monoclonal antibodies were subsequently examined for their ability to block receptor auto-phosphorylation and inhibit in vitro cellular proliferation: the mouse monoclonal antibody αIR3 and the fully human monoclonal antibody A12 (ImClone Systems). In MCF7 cells, IGF-induced receptor auto-phosphorylation was inhibited by pre-exposure to both αIR3 and A12. In monolayer culture, both antibodies inhibited proliferation ranging from 30-50% of control at three days in SCC1483, SCC6, PC3, MCF7 and H226 cells. Minimal antiproliferative effects (less than 20%) were observed for T98G, A549, DU145, SCC1 and SCC22B cells. Beyond three days, time course experiments with SCC1 cells demonstrated significant antiproliferative activity of αIR3 at 6 and 9 days. No correlation was found between the level of IGF-1R expression and the degree of proliferation inhibition by either antibody. To determine the antiproliferative efficacy of combined epidermal growth factor receptor (EGFR) and IGF-1R blockade, dual inhibitor assays were carried out with αIR3 and the humanized anti-EGFR monoclonal antibody cetuximab (ImClone Systems). H226 cells exposed to combined EGFR and IGF-1R blockade for four days demonstrated significantly higher proliferation inhibition (82%) compared to either EGFR or IGF-1R inhibition alone (68% and 28%, respectively). Further work examining the capability for IGF-1R inhibition to enhance the cytotoxicity of chemotherapeutic agents and radiation are ongoing. These results validate IGF-1R as a therapeutic target and highlight the anti-cancer potential for IGF-1R inhibitors in combination molecular therapy.