EGFR and IGF1R Inhibition in Head and Neck Cutaneous Squamous Cell Carcinoma

Abstract

Objective: 1) Determine if upregulation of insulin-like growth factor receptor (IGF1R) correlates with resistance to epidermal growth factor receptor (EGFR) inhibitors in patients with head and neck cutaneous squamous cell carcinoma (cSCCHN). 2) Evaluate the effect of combined inhibition of EGFR and IGF1R with tyrosine kinase inhibitors in cSCCHN.

Method: cSCC cell lines MET1, MET4, SCC12, and SCC13 were treated with the EGFR inhibitor erlotinib and/or the IGF1R inhibitor picropodophyllin, then evaluated for cell growth and expression of EGFR, IGF1R, and downstream signaling molecules. cSCCHN patient specimens were evaluated with antibodies for EGFR, IGF1R, phospho-Akt, and phospho-MAPK.

Results: Comparison of normal skin to cSCCHN specimens showed overexpression of EGFR (P = .0008) and IGF1R (P = .041). Treatment with erlotinib or picropodophyllin inhibited receptor phosphorylation (P < .01) and showed dose-dependent inhibition of cell growth in all cell lines. At intermediate concentrations, treatment with both inhibitors inhibited cell growth more effectively than either inhibitor alone (P < .05). Dual inhibition also decreased downstream activation of both Akt (P < .006) and p42/44 MAPK (P < .01). Specimens from a patient whose cSCCHN developed resistance to an EGFR inhibitor showed upregulation of IGF1R (P < .0001) and phosphorylated Akt (P < .01) compared to this same tumor prior to treatment with EGFR inhibitor.

Conclusion: Upregulation of IGF1R may be a pathway for resistance to EGFR inhibition in cSCCHN, possibly via increased Akt activation. Dual inhibition of EGFR and IGF1R inhibits cSCCHN cell growth more effectively than either inhibitor alone, suggesting that combination therapy with both inhibitors may be a promising therapeutic strategy for cSCCHN.