Replication stress leading to apoptosis within the S-phase contributes to synergism between vorinostat and AZD1775 in HNSCC harboring high-risk TP53 mutation
Journal
Clinical Cancer Research
Journal Volume
23
Journal Issue
21
Pages
6541
Date Issued
2017-11-01
Author(s)
Tanaka, Noriaki
Patel, Ameeta A.
Tang, Lin
Silver, Natalie L.
Lindemann, Antje
Takahashi, Hideaki
Jaksik, Roman
Rao, Xiayu
Kalu, Nene N.
Wang, Jiping
Frederick, Mitchell J.
Johnson, Faye
Gleber-Netto, Frederico O.
Fu, Siqing
Kimmel, Marek
Wang, Jing
Hittelman, Walter N.
Pickering, Curtis R.
Myers, Jeffrey N.
Osman, Abdullah A.
Abstract
Purpose: The cure rate for patients with advanced head and neck squamous cell carcinoma (HNSCC) remains poor due to resistance to standard therapy primarily consisting of chemoradiation. As mutation of TP53 in HNSCC occurs in 60% to 80% of non–HPV-associated cases and is in turn associated with resistance to these treatments, more effective therapies are needed. In this study, we evaluated the efficacy of a regimen combining vorinostat and AZD1775 in HNSCC cells with a variety of p53 mutations. Experimental Design: Clonogenic survival assays and an orthotopic mouse model of oral cancer were used to examine the in vitro and in vivo sensitivity of high-risk mutant p53 HNSCC cell lines to vorinostat in combination with AZD1775. Cell cycle, replication stress, homologous recombination (HR), live cell imaging, RNA sequencing, and apoptosis analyses were performed to dissect molecular mechanisms. Results: We found that vorinostat synergizes with AZD1775 in vitro to inhibit growth of HNSCC cells harboring high-risk mutp53. These drugs interact synergistically to induce DNA damage, replication stress associated with impaired Rad51-mediated HR through activation of CDK1, and inhibition of Chk1 phosphorylation, culminating in an early apoptotic cell death during the S-phase of the cell cycle. The combination of vorinostat and AZD1775 inhibits tumor growth and angiogenesis in vivo in an orthotopic mouse model of oral cancer and prolongs animal survival. Conclusions: Vorinostat synergizes with AZD1775 in HNSCC cells with mutant p53 in vitro and in vivo. A strategy combining HDAC and WEE1 inhibition deserves further clinical investigation in patients with advanced HNSCC.
Subjects
HISTONE DEACETYLASE INHIBITORS; SQUAMOUS-CELL CARCINOMA; EVOLUTIONARY ACTION SCORE; NECK-CANCER; HOMOLOGOUS RECOMBINATION; MITOTIC CATASTROPHE; HDAC INHIBITORS; OVARIAN-CANCER; MOUSE MODEL; MUTANT P53
SDGs
Publisher
AMER ASSOC CANCER RESEARCH
Type
journal article