Synergistic combination of flavopiridol and carfilzomib targets commonly dysregulated pathways in adrenocortical carcinoma and has biomarkers of response
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Naris Nilubol1, Myriem Boufraqech1, Lisa Zhang1, Kelli Gaskins1, Min Shen2, Ya-Qin Zhang2, Sudheer K. Gara1, Christopher P. Austin2 and Electron Kebebew1,3
1Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
2National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA
3Department of Surgery, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA
Naris Nilubol, email: email@example.com
Keywords: adrenocortical carcinoma; flavopiridol; carfilzomib; X-linked Inhibitor of apoptosis; high-throughput screening
Received: May 25, 2018 Accepted: July 29, 2018 Published: August 31, 2018
Drug repurposing is an effective approach to identify active drugs with known toxicity profiles for rare cancers such as ACC. The objective of this study was to determine the anticancer activity of combination treatment for ACC from previously identified candidate agents using quantitative high-throughput screening (qHTS). In this study, we evaluated the anticancer activity of flavopiridol and carfilzomib in three ACC cell lines in vitro and in vivo. Human ACC samples were analyzed for drug-target analysis, and cancer-related pathway arrays were used to identify biomarkers of treatment response. Because flavopiridol is a potent cyclin-dependent kinase (CDK) inhibitor, we found significantly higher CDK1 and CDK2 mRNA expression in three independent cohorts human ACC (p<0.01) and CDK1 protein by immunohistochemistry (p<0.01) in human ACC samples. In vitro treatment with flavopiridol and carfilzomib in all three ACC cell lines resulted in a dose-dependent, anti-proliferative effect, and the combination had synergistic activity as well as in three-dimensional tumor spheroids. We observed increased G2M cell-cycle arrest and apoptosis with combination treatment compared to other groups in vitro. The combination treatment decreased XIAP protein expression in ACC cell lines. Mice with human ACC xenografts treated with flavopiridol and carfilzomib had significantly lower tumor burden, compared to other groups (p<0.05). We observed increased cleaved-caspase expression and decreased XIAP in tumor xenografts of mice treated with combined agents. Our preclinical data supports the evaluation of combination therapy with flavopiridol and carfilzomib in patients with advanced ACC.
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