TY - JOUR
T1 - Dual inhibition of HDAC and EGFR signaling with CUDC-101 induces potent suppression of tumor growth and metastasis in anaplastic thyroid cancer
AU - Zhang, Lisa
AU - Zhang, Yaqin
AU - Mehta, Amit
AU - Boufraqech, Myriem
AU - Davis, Sean
AU - Wang, Jing
AU - Tian, Ze
AU - Yu, Zhiya
AU - Boxer, Matthew B.
AU - Kiefer, Jeffrey A.
AU - Copland, John A.
AU - Smallridge, Robert C.
AU - Li, Zhuyin
AU - Shen, Min
AU - Kebebew, Electron
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - Anaplastic thyroid cancer
KW - CUDC-101
KW - EGFR
KW - HDAC
KW - Quantitative high-throughput screening
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U2 - 10.18632/oncotarget.3268
DO - 10.18632/oncotarget.3268
M3 - Article
C2 - 25940539
AN - SCOPUS:84928745211
SN - 1949-2553
VL - 6
SP - 9073
EP - 9085
JO - Oncotarget
JF - Oncotarget
IS - 11
ER -