Molecular and Cellular Pathobiology Enhanced Radiation Sensitivity in HPV-Positive Head and Neck Cancer

Patients with human papillomavirus (HPVþ)–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 HPVþHNC cell lines and a series of HPV HNC cell lines using in vitro and in vivo techniques. HPVþHNCs exhibited greater intrinsic radiation sensitivity (average SF2 HPV : 0.59 vs. HPVþ: 0.22; P < 0.0001), corresponding with a prolonged G2–M cell-cycle arrest and increased apoptosis following radiation exposure (percent change 0% vs. 85%; P1⁄4 0.002). A genome-widemicroarraywas used to compare gene expression 24 hours following radiation between HPVþ and HPV cell lines. Multiple genes in TP53 pathway were upregulated in HPVþ cells (Z score 4.90), including a 4.6-fold increase in TP53 (P < 0.0001). Using immortalized human tonsillar epithelial (HTE) cells, increased radiation sensitivity was seen in cell expressingHPV-16 E6 despite the effect of E6 to degrade p53. This suggested that low levels of normally functioning p53 in HPVþHNC cells could be activated by radiation, leading to cell death. Consistent with this, more complete knockdown of TP53 by siRNA resulted in radiation resistance. These results provide clear evidence, and a supporting mechanism, for increased radiation sensitivity inHPVþHNC relative toHPV HNC. This issue is under active investigation in a series of clinical trials attempting to de-escalate radiation (and chemotherapy) in selected patients with HPVþ HNC in light of their favorable overall survival outcome. Cancer Res; 73(15); 4791–800. 2013 AACR.