1. HSP90 inhibition sensitizes head and neck cancer to platin-based chemoradiotherapy by modulation of the DNA damage response resulting in chromosomal fragmentation.
- Author
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McLaughlin M, Barker HE, Khan AA, Pedersen M, Dillon M, Mansfield DC, Patel R, Kyula JN, Bhide SA, Newbold KL, Nutting CM, and Harrington KJ
- Subjects
- Animals, BRCA1 Protein genetics, Carcinoma, Squamous Cell drug therapy, Carcinoma, Squamous Cell genetics, Carcinoma, Squamous Cell metabolism, Carcinoma, Squamous Cell radiotherapy, Cell Line, Tumor, Chemoradiotherapy methods, Chromosomes genetics, DNA Damage genetics, DNA Damage radiation effects, DNA Repair drug effects, DNA Repair genetics, DNA Repair radiation effects, Female, Head and Neck Neoplasms genetics, Head and Neck Neoplasms metabolism, Head and Neck Neoplasms radiotherapy, Homologous Recombination drug effects, Humans, Mice, Inbred BALB C, Mice, Nude, Protein Kinase Inhibitors pharmacology, Squamous Cell Carcinoma of Head and Neck, Tumor Suppressor Protein p53 genetics, Chromosomes drug effects, DNA Damage drug effects, DNA Fragmentation drug effects, HSP90 Heat-Shock Proteins antagonists & inhibitors, Head and Neck Neoplasms drug therapy, Isoxazoles pharmacology, Organoplatinum Compounds pharmacology, Resorcinols pharmacology
- Abstract
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.
- Published
- 2017
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