Effect of insulin-like growth factor 1 receptor inhibitor on sensitization of head and neck cancer cells to cetuximab and methotrexate
6079 Background: Insulin-like growth factor 1 receptor (IGF1R) is highly expressed in head and neck squamous cell carcinoma (HNSCC) and IGF1R inhibitors have been shown to modulate sensitivity to selected chemotherapeutic agents and radiation. The combination effects of an IGF1R inhibitor, MK-0646, with cetuximab or cytotoxic agents that are commonly used in the treatment of recurrent and/or metastatic HNSCC were examined in cetuximab resistant and sensitive HNSCC cell lines. Methods: The cell lines, SCC1 and its cetuximab-resistant clone 1Cc8, were treated with MK-0646, cetuximab or methotrexate, and a combination of MK-0646 and each anti-cancer drug (MK-0646 was supplied by Merck & Co., Inc.). The effect of treatments on cell proliferation and anti-tumor activity was determined using MTS assay in vitro and in vivo using mouse xenografts generated from the cell lines. Overall changes in the gene and protein expressions with the treatments were determined by DNA microarrays and western blots. Results: The IGF1R inhibitor, MK-0646, showed high-sensitivity in vitro xenograft model in SCC1 as monotherapy and increased sensitivity to cetuximab in SCC1 and to methotrexate in 1Cc8 in combination. However, MK-0646 did not inhibit cell proliferation in vitro and in vivo in 1Cc8. The gene expression array and western blot analyses showed that MK-0646 decreased expression of AKT and dihydrofolate reductase (DHFR), a target of methotrexate. Increased expressions of AKT and DHFR have been shown to associate with cetuximab and methotrexate resistance as well as radiation resistance. Conclusions: The development of tolerance in response to the IGF1R inhibitor and cetuximab is common. Whereas IGF1R inhibitors may have little therapeutic impact in cetuximab resistant, the IGF1R inhibitor may modulate response to selected chemotherapeutic agents and to radiation. The IGF1R inhibitor appears to enhance cetuximab and methotrexate response, and modulates genes associated with radiation resistance thereby providing alternative regimens for recurrent and refractory HNSCC patients who have developed resistance to initial therapies. No significant financial relationships to disclose.