title: TP53 disruptive mutations lead to head and neck cancer treatment failure through inhibition of radiation-induced senescence.
abstract: OBJECTIVE
  Mortality of patients with head and neck squamous cell carcinoma (HNSCC) is primarily driven by tumor cell radioresistance leading to locoregional recurrence (LRR). In this study, we use a classification of TP53 mutation (disruptive vs. nondisruptive) and examine impact on clinical outcomes and radiation sensitivity.
  
  
  METHODS
  Seventy-four patients with HNSCC treated with surgery and postoperative radiation and 38 HNSCC cell lines were assembled; for each, TP53 was sequenced and the in vitro radioresistance measured using clonogenic assays. p53 protein expression was inhibited using short hairpin RNA (shRNA) and overexpressed using a retrovirus. Radiation-induced apoptosis, mitotic cell death, senescence, and reactive oxygen species (ROS) assays were carried out. The effect of the drug metformin on overcoming mutant p53-associated radiation resistance was examined in vitro as well as in vivo, using an orthotopic xenograft model.
  
  
  RESULTS
  Mutant TP53 alone was not predictive of LRR; however, disruptive TP53 mutation strongly predicted LRR (P = 0.03). Cell lines with disruptive mutations were significantly more radioresistant (P < 0.05). Expression of disruptive TP53 mutations significantly decreased radiation-induced senescence, as measured by SA-β-gal staining, p21 expression, and release of ROS. The mitochondrial agent metformin potentiated the effects of radiation in the presence of a disruptive TP53 mutation partially via senescence. Examination of our patient cohort showed that LRR was decreased in patients taking metformin.
  
  
  CONCLUSIONS
  Disruptive TP53 mutations in HNSCC tumors predicts for LRR, because of increased radioresistance via the inhibition of senescence. Metformin can serve as a radiosensitizer for HNSCC with disruptive TP53, presaging the possibility of personalizing HNSCC treatment.
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Heath D
authors.initials: HD
authors.lastname: Skinner
authors.forename: Vlad C
authors.initials: VC
authors.lastname: Sandulache
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Ow
authors.forename: Raymond E
authors.initials: RE
authors.lastname: Meyn
authors.forename: John S
authors.initials: JS
authors.lastname: Yordy
authors.forename: Beth M
authors.initials: BM
authors.lastname: Beadle
authors.forename: Alison L
authors.initials: AL
authors.lastname: Fitzgerald
authors.forename: Uma
authors.initials: U
authors.lastname: Giri
authors.forename: K Kian
authors.initials: KK
authors.lastname: Ang
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Myers
mesh_terms: D000375:Aging / Q000235:genetics / Q000528:radiation effects*; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000401:mortality / Q000532:radiotherapy; D005455:Fluorescent Antibody Technique; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000401:mortality / Q000532:radiotherapy; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality; D011836:Radiation Tolerance / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015996:Survival Rate; D017211:Treatment Failure; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
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