HSP90 inhibition sensitizes head and neck cancer to platin-based chemoradiotherapy by modulation of the DNA damage response resulting in chromosomal fragmentation.
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Date
2017-01-31Author
McLaughlin, M
Barker, HE
Khan, AA
Pedersen, M
Dillon, M
Mansfield, DC
Patel, R
Kyula, JN
Bhide, SA
Newbold, KL
Nutting, CM
Harrington, KJ
Type
Journal Article
Metadata
Show full item recordAbstract
BACKGROUND: Concurrent cisplatin radiotherapy (CCRT) is a current standard-of-care for locally advanced head and neck squamous cell carcinoma (HNSCC). However, CCRT is frequently ineffective in patients with advanced disease. It has previously been shown that HSP90 inhibitors act as radiosensitizers, but these studies have not focused on CCRT in HNSCC. Here, we evaluated the HSP90 inhibitor, AUY922, combined with CCRT. METHODS: The ability of AUY922 to sensitize to CCRT was assessed in p53 mutant head and neck cell lines by clonogenic assay. Modulation of the CCRT induced DNA damage response (DDR) by AUY922 was characterized by confocal image analysis of RAD51, BRCA1, 53BP1, ATM and mutant p53 signaling. The role of FANCA depletion by AUY922 was examined using shRNA. Cell cycle checkpoint abrogation and chromosomal fragmentation was assessed by western blot, FACS and confocal. The role of ATM was also assessed by shRNA. AUY922 in combination with CCRT was assessed in vivo. RESULTS: The combination of AUY922 with cisplatin, radiation and CCRT was found to be synergistic in p53 mutant HNSCC. AUY922 leads to significant alterations to the DDR induced by CCRT. This comprises inhibition of homologous recombination through decreased RAD51 and pS1524 BRCA1 with a corresponding increase in 53BP1 foci, activation of ATM and signaling into mutant p53. A shift to more error prone repair combined with a loss of checkpoint function leads to fragmentation of chromosomal material. The degree of disruption to DDR signalling correlated to chromosomal fragmentation and loss of clonogenicity. ATM shRNA indicated a possible rationale for the combination of AUY922 and CCRT in cells lacking ATM function. CONCLUSIONS: This study supports future clinical studies combining AUY922 and CCRT in p53 mutant HNSCC. Modulation of the DDR and chromosomal fragmentation are likely to be analytical points of interest in such trials.
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Subject
Cell Line, Tumor
Chromosomes
Animals
Mice, Inbred BALB C
Humans
Mice, Nude
Carcinoma, Squamous Cell
Head and Neck Neoplasms
DNA Damage
Organoplatinum Compounds
Resorcinols
Isoxazoles
BRCA1 Protein
Protein Kinase Inhibitors
DNA Fragmentation
DNA Repair
Female
Tumor Suppressor Protein p53
HSP90 Heat-Shock Proteins
Chemoradiotherapy
Homologous Recombination
Squamous Cell Carcinoma of Head and Neck
Research team
Targeted Therapy
Language
eng
Date accepted
2017-01-23
License start date
2017-01-31
Citation
BMC cancer, 2017, 17 (1), pp. 86 - ?
Publisher
BIOMED CENTRAL LTD