Abstract
BackgroundConcurrent 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.MethodsThe 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.ResultsThe 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.ConclusionsThis 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.
Highlights
Concurrent cisplatin radiotherapy (CCRT) is a current standard-of-care for locally advanced head and neck squamous cell carcinoma (HNSCC)
AUY922 sensitizes p53mt HNSCC to cisplatin, radiation and concurrent-cisplatin radiotherapy (CCRT) The ability of AUY922 to sensitize to cisplatin, radiation and CCRT was assessed in a panel of cell lines by clonogenic assay using the scheduling outlined (Fig. 1a)
In exploring the role the Homologous recombination (HR) component FANCA may play in HSP90 chemosensitization, we discovered a profound increase in ATM foci in response to AUY922
Summary
Concurrent cisplatin radiotherapy (CCRT) is a current standard-of-care for locally advanced head and neck squamous cell carcinoma (HNSCC). Concurrent cisplatin radiotherapy (CCRT) is a standardof-care for patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Despite improving outcomes with CCRT, patients with locally-advanced HNSCC have a poor prognosis. HSP90 is a molecular chaperone involved in the initial folding and continued conformational maintenance of a pool of client proteins. Many of these have been identified as oncoproteins or key components in repair and cell cycle arrest following exposure to DNA damaging agents [3,4,5]. HSP90 inhibitors mediate sensitization through multifaceted effects and radiosensitize a broad range of genetically diverse tumor types [6,7,8,9,10,11,12]
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