TP53 disruptive mutations lead to head and neck cancer treatment failure through inhibition of radiation-induced senescence

Heath D. Skinner, Vlad C. Sandulache, Thomas J. Ow, Raymond E. Meyn, John S. Yordy, Beth M. Beadle, Alison L. Fitzgerald, Uma Giri, K. Kian Ang, Jeffrey N. Myers

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Abstract

Purpose: 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. Experimental Design: 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-b-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.

Original languageEnglish (US)
Pages (from-to)290-300
Number of pages11
JournalClinical Cancer Research
Volume18
Issue number1
DOIs
StatePublished - Jan 1 2012

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Head and Neck Neoplasms
Treatment Failure
Metformin
Radiation
Mutation
Recurrence
Reactive Oxygen Species
Cell Line
Cell Aging
Radiation Tolerance
Radiation Effects
Retroviridae
Heterografts
Small Interfering RNA
Carcinoma, squamous cell of head and neck
Neoplasms
Cell Death
Research Design
Apoptosis
Staining and Labeling

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Skinner, H. D., Sandulache, V. C., Ow, T. J., Meyn, R. E., Yordy, J. S., Beadle, B. M., ... Myers, J. N. (2012). TP53 disruptive mutations lead to head and neck cancer treatment failure through inhibition of radiation-induced senescence. Clinical Cancer Research, 18(1), 290-300. https://doi.org/10.1158/1078-0432.CCR-11-2260

TP53 disruptive mutations lead to head and neck cancer treatment failure through inhibition of radiation-induced senescence. / Skinner, Heath D.; Sandulache, Vlad C.; Ow, Thomas J.; Meyn, Raymond E.; Yordy, John S.; Beadle, Beth M.; Fitzgerald, Alison L.; Giri, Uma; Ang, K. Kian; Myers, Jeffrey N.

In: Clinical Cancer Research, Vol. 18, No. 1, 01.01.2012, p. 290-300.

Research output: Contribution to journalArticle

Skinner, HD, Sandulache, VC, Ow, TJ, Meyn, RE, Yordy, JS, Beadle, BM, Fitzgerald, AL, Giri, U, Ang, KK & Myers, JN 2012, 'TP53 disruptive mutations lead to head and neck cancer treatment failure through inhibition of radiation-induced senescence', Clinical Cancer Research, vol. 18, no. 1, pp. 290-300. https://doi.org/10.1158/1078-0432.CCR-11-2260
Skinner, Heath D. ; Sandulache, Vlad C. ; Ow, Thomas J. ; Meyn, Raymond E. ; Yordy, John S. ; Beadle, Beth M. ; Fitzgerald, Alison L. ; Giri, Uma ; Ang, K. Kian ; Myers, Jeffrey N. / TP53 disruptive mutations lead to head and neck cancer treatment failure through inhibition of radiation-induced senescence. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 1. pp. 290-300.
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AU - Ow, Thomas J.

AU - Meyn, Raymond E.

AU - Yordy, John S.

AU - Beadle, Beth M.

AU - Fitzgerald, Alison L.

AU - Giri, Uma

AU - Ang, K. Kian

AU - Myers, Jeffrey N.

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N2 - Purpose: 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. Experimental Design: 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-b-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.

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