Back ground: Insulin-like growth factor-1 receptor (IGF1R) activity is upregulated in a variety of human cancers and IGF1R signaling has been implicated as a mechanism of resistance to various cancer therapies, including radiotherapy, cytotoxic chemotherapy, and targeted molecular therapy. We have demonstrated that IGF1R activation can induce resistance to targeted therapy of head and neck squamous cell carcinomas (HNSCCs) using epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Targeting the IGF1R by selective small molecule kinase inhibition may thus hold promise as an adjuvant treatment for HNSCC.

Aims: (1) To assess the anti-tumor effects of two IGF1R/insulin receptor TKIs, BMS-754807 and OSI-906, in multiple HNSCC cell lines in vitro. (2) To evaluate the effect of combined IGF1R and EGFR inhibition in HNSCC cell lines in vitro.

Methods: The effect of IGF1R inhibition on cell proliferation, viability, survival, and apoptosis was assessed using alamarBlue, trypan blue exclusion, clonogenic, and flow cytometric assays in 9 HNSCC cell lines. Alterations in downstream IGF1R signaling were assessed by standard immunoblot. The impact of combining an EGFR-TKI with an IGF1R-TKI was measured.

Result: Both BMS-754807 and OSI-906 inhibited IGF1R phosphorylation at 200 nM. Complete inhibition of the phosphorylation of IRS-1 and Akt required higher concentrations. Both inhibitors slowed proliferation, decreased cell viability, and decreased cell survival in all 9 cell lines. The EC50 to inhibit proliferation was in the range of X to X microM for BMS-754807 and X to X microM for OSI-906. Both drugs induced apoptosis in HNSCC tumor cell lines based on flow cytometric analysis of caspase-3 cleavage and PARP cleavage. In combination with gefitinib and lapatinib, BMS-754807 and OSI-906 were capable of synergistic growth inhibition.

Conclusion: Inhibition of IGF1R activity using the selective TKIs BMS-754807 and OSI906 has an antitumor effect on HNSCC cells in vitro. These drugs are synergistic with EGFR-TKIs and co-targeting the two receptors may represent an approach to overcoming clinical resistance to targeted anti-growth factor therapy in HNSCC.

Citation Format: Ashraf A. Khalil, Mark J. Axelrod, Matthew A. Hubbard, Anne K. Maxwell, Linnea E. Taniguchi, Rolando E. Mendez, Mark J. Jameson. Anti-tumor effect of insulin-like growth factor-1 receptor inhibition in head and neck squamous cell carcinoma. [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 2945. doi:10.1158/1538-7445.AM2013-2945

©2013 American Association for Cancer Research
2013