Growth inhibition and radiosensitization of human papillomavirus (HPV) positive head and neck cancer (HNC) by epidermal growth factor receptor inhibition is mediated by apoptosis

Abstract

PURPOSETo determine the mechanism by which HPV+ HNC cells and patient‐derived tumorgrafts are sensitive to growth inhibition and/or radiosensitization by cetuximab.METHODSFour cell lines and several direct‐from‐patient tumorgrafts validated for HPV expression were used in a subcutaneous flank approach using athymic Foxn1nu female mice. Apoptosis and cell cycle distribution were assessed by caspase activation, flow cytometry, and western blot.RESULTSCetuximab caused significant delay in cell proliferation (p<0.005), decrease in colony formation (p<0.026), and minimal radiosensitization. In both a cell line xenograft and a direct‐from‐patient tumorgraft model of HPV+ HNCs cetuximab resulted in significant tumor growth delay (median time to tumor quadrupling: 15 vs. 24 days, p=0.02; and 42 vs. 89 days, p=0.0001, respectively). When combined with radiation, cetuximab resulted in a significant increase in time to tumor quadrupling compared to either cetuximab or radiation alone (p<0.001). Cetuximab's effects correlated with enhanced apoptosis and a G1 cell cycle arrest.CONCLUSIONSCetuximab is active against HPV+ HNC cells and primary tumors and shows modest radiosensitization. Increased apoptosis was seen following cetuximab treatment. Mechanisms of resistance and predictors of response to EGFR inhibition in HPV+ HNC are being investigated.