Premium
Growth inhibition and radiosensitization of human papillomavirus (HPV) positive head and neck cancer (HNC) by epidermal growth factor receptor inhibition is mediated by apoptosis
Author(s) -
Kimple Randall J,
Smith Molly A,
Blitzer Grace C,
Huang HaoShun,
Torres Alexandra D
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1105.16
Subject(s) - cetuximab , apoptosis , cancer research , medicine , epidermal growth factor receptor , flow cytometry , cell cycle , growth inhibition , cell growth , head and neck cancer , western blot , oncology , cancer , biology , immunology , colorectal cancer , biochemistry , genetics , gene
PURPOSE To determine the mechanism by which HPV+ HNC cells and patient‐derived tumorgrafts are sensitive to growth inhibition and/or radiosensitization by cetuximab. METHODS Four 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. RESULTS Cetuximab 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. CONCLUSIONS Cetuximab 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.