Data from Enhanced Radiation Sensitivity in HPV-Positive Head and Neck Cancer

Abstract

<div>Abstract<p>Patients with human papillomavirus (HPV+)–associated head and neck cancer (HNC) show significantly improved survival outcome compared with those with HPV-negative (HPV−) tumors. Published data examining this difference offers conflicting results to date. We systematically investigated the radiation sensitivity of all available validated HPV+ HNC cell lines and a series of HPV− HNC cell lines using <i>in vitro</i> and <i>in vivo</i> techniques. HPV+ HNCs exhibited greater intrinsic radiation sensitivity (average SF2 HPV−: 0.59 vs. HPV+: 0.22; <i>P</i> < 0.0001), corresponding with a prolonged G<sub>2</sub>–M cell-cycle arrest and increased apoptosis following radiation exposure (percent change 0% vs. 85%; <i>P</i> = 0.002). A genome-wide microarray was used to compare gene expression 24 hours following radiation between HPV+ and HPV− cell lines. Multiple genes in <i>TP53</i> pathway were upregulated in HPV+ cells (Z score 4.90), including a 4.6-fold increase in <i>TP53</i> (<i>P</i> < 0.0001). Using immortalized human tonsillar epithelial (HTE) cells, increased radiation sensitivity was seen in cell expressing HPV-16 E6 despite the effect of E6 to degrade p53. This suggested that low levels of normally functioning p53 in HPV+ HNC cells could be activated by radiation, leading to cell death. Consistent with this, more complete knockdown of <i>TP53</i> by siRNA resulted in radiation resistance. These results provide clear evidence, and a supporting mechanism, for increased radiation sensitivity in HPV+ HNC relative to HPV− HNC. This issue is under active investigation in a series of clinical trials attempting to de-escalate radiation (and chemotherapy) in selected patients with HPV+ HNC in light of their favorable overall survival outcome. <i>Cancer Res; 73(15); 4791–800. ©2013 AACR</i>.</p></div>