Abstract
Anaplastic thyroid cancer (ATC) is one of the most lethal human malignancies that currently has no effective therapy. We performed quantitative high-throughput screening (qHTS) in three ATC cell lines using 3,282 clinically approved drugs and drug candidates, and identified 100 active agents. Enrichment analysis of active compounds showed that inhibitors of EGFR and histone deacetylase (HDAC) were most active. Of these, the first-in-class dual inhibitor of EGFR, HER2 and HDACs, CUDC-101, had the highest efficacy and lower IC50 than established drugs. We validated that CUDC-101 inhibited cellular proliferation and resulted in cell death by inducing cell cycle arrest and caspase-dependent apoptosis. CUDC-101 also inhibited cellular migration in vitro. Mechanistically, CUDC-101 inhibited MAPK signaling and histone deacetylation in ATC cell lines with multiple driver mutations present in human ATC. The anticancer effect of CUDC-101 was associated with increased expression of p21 and E-cadherin, and reduced expression of survivin, XIAP, β-catenin, N-cadherin, and Vimentin. In an in vivo mouse model of metastatic ATC, CUDC-101 inhibited tumor growth and metastases, and significantly prolonged survival. Response to CUDC-101 treatment in vivo was associated with increased histone 3 acetylation and reduced survivin expression. Our findings provide a preclinical basis to evaluate CUDC-101 therapy in ATC.
Highlights
Anaplastic thyroid cancer (ATC) is one of the most lethal human malignancies
We investigated whether CUDC-101 had any effect on cellular migration because ATC is a highly invasive cancer and the epidermal growth factor receptor (EGFR)/RAS/BRAF/MEK/ERK pathway has been shown to regulate cellular migration and epithelial-mesenchymal transition (EMT) [21,22,23]
CUDC-101 is thought to be a dual histone deacetylase (HDAC), EGFR, and HER2 inhibitor; we examined its inhibitory effect on HDAC and EGFR downstream pathways in ATC cells [24]
Summary
Anaplastic thyroid cancer (ATC) is one of the most lethal human malignancies. It accounts for less than 2% of all thyroid cancers, but results in nearly one-third of thyroid cancer–related deaths [1]. Drug discovery and development are costly and time-consuming, and rarely focused on rare malignancies This is partly because it takes an average of 15 years and costs approximately $800 million to bring a single drug to market; this cost would not be recouped for rare cancer indications. There are several advantages to using this strategy, including knowledge of the drug’s pharmacokinetics, pharmacodynamics, and side effects These data can lead to a more streamlined translation of any promising preclinical findings into Phase II and/or III clinical trials to test the efficacy of the compound. Another advantage of this approach is the ability to determine whether the compound(s) identified from qHTS could effectively target known molecules or pathways that are altered in a given cancer type. Agents identified by qHTS could be tested to evaluate their effects on these known activated pathways
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