Carfilzomib potentiates CUDC-101-induced apoptosis in anaplastic thyroid cancer

// Lisa Zhang 1 , Myriem Boufraqech 1 , Ross Lake 2 and Electron Kebebew 1 1 Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA 2 Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, Bethesda, Maryland, USA Correspondence to: Electron Kebebew, email: // Keywords : carfilzomib, CUDC-101, anaplastic thyroid cancer, combination therapy, apoptosis Received : December 16, 2015 Accepted : February 08, 2016 Published : February 26, 2016 Abstract Anaplastic thyroid cancer (ATC) is one of the most aggressive human malignancies, with no effective treatment currently available. Previously, we identified agents active against ATC cells, both in vitro and in vivo , using quantitative high-throughput screening of 3282 clinically approved drugs and small molecules. Here, we report that combining two of these active agents, carfilzomib, a second-generation proteasome inhibitor, and CUDC-101, a histone deacetylase and multi-kinase inhibitor, results in increased, synergistic activity in ATC cells. The combination of carfilzomib and CUDC-101 synergistically inhibited cellular proliferation and caused cell death in multiple ATC cell lines harboring various driver mutations observed in human ATC tumors. This increased anti-ATC effect was associated with a synergistically enhanced G2/M cell cycle arrest and increased caspase 3/7 activity induced by the drug combination. Mechanistically, treatment with carfilzomib and CUDC-101 increased p21 expression and poly (ADP-ribose) polymerase protein cleavage. Our results suggest that combining carfilzomib and CUDC-101 would offer an effective therapeutic strategy to treat ATC.