Anaplastic thyroid cancer (ATC) is one of the most aggressive human
malignancies. Currently, there is no standard or effective
therapy for ATC. Drug repurposing for
cancer treatment is an emerging approach for identifying compounds that may have
antineoplastic effects. The aim of this study was to use high-throughput drug library screening to identify and subsequently validate novel therapeutic agents with anticancer effects in ATC. We performed quantitative high-throughput screening (qHTS) in ATC cell lines (SW-1736, 8505C, and C-643), using a compound library of 3282 drugs. qHTS identified 100 compounds that were active in all three ATC cell lines.
Proteasome inhibitors were one of the most active drug categories according to enrichment analysis. Of the three
proteasome inhibitors screened, a second-generation
proteasome inhibitor,
carfilzomib, was the most active. Treatment of ATC cells with
carfilzomib significantly inhibited cellular proliferation and induced G2/M cell cycle arrest and caspase-dependent apoptosis. Mechanistically,
carfilzomib increased expression of p27 (CDKN1B) and decreased expression of the
anti-apoptotic protein ATF4. Pretreatment with
carfilzomib reduced in vivo
metastases (lung, bone, liver, and kidney) and
disease progression, and decreased
N-cadherin expression.
Carfilzomib treatment of mice with established, widely metastatic disease significantly increased their survival, without significant toxicity. Our findings support the use or clinical study of
carfilzomib as a therapeutic option in patients with advanced and metastatic ATC.