title: Enhanced radiation sensitivity in HPV-positive head and neck cancer.
abstract: 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 in vitro and in vivo techniques. HPV+ HNCs exhibited greater intrinsic radiation sensitivity (average SF2 HPV-: 0.59 vs. HPV+: 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%; P = 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 TP53 pathway were upregulated in HPV+ 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 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 TP53 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.
authors.affiliation: Department of Human Oncology, University of Wisconsin Comprehensive Cancer Center, 3107 WIMR, 1111 Highland Avenue, Madison, WI 53705, USA. rkimple@humonc.wisc.edu
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Kimple
authors.forename: Molly A
authors.initials: MA
authors.lastname: Smith
authors.forename: Grace C
authors.initials: GC
authors.lastname: Blitzer
authors.forename: Alexandra D
authors.initials: AD
authors.lastname: Torres
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Martin
authors.forename: Robert Z
authors.initials: RZ
authors.lastname: Yang
authors.forename: Chimera R
authors.initials: CR
authors.lastname: Peet
authors.forename: Laurel D
authors.initials: LD
authors.lastname: Lorenz
authors.forename: Kwangok P
authors.initials: KP
authors.lastname: Nickel
authors.forename: Aloysius J
authors.initials: AJ
authors.lastname: Klingelhutz
authors.forename: Paul F
authors.initials: PF
authors.lastname: Lambert
authors.forename: Paul M
authors.initials: PM
authors.lastname: Harari
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects; D045744:Cell Line, Tumor; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000821:virology*; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D030361:Papillomavirus Infections / Q000150:complications*; D011836:Radiation Tolerance / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*; D023041:Xenograft Model Antitumor Assays
chemical_list: D016159:Tumor Suppressor Protein p53