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Oncotarget. 2015 Apr 20;6(11):9073-85.

Dual inhibition of HDAC and EGFR signaling with CUDC-101 induces potent suppression of tumor growth and metastasis in anaplastic thyroid cancer.

Author information

1
Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
2
Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA.
3
Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.
4
Cancer Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
5
Curis Inc., Translational Science, Lexington, MA, USA.
6
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
7
Division of Information Sciences, Translational Genomics Research Institute, Phoenix, AZ, USA.
8
Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
9
Endocrinology Division, Internal Medicine Department, Mayo Clinic, Jacksonville, FL, USA.

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.

KEYWORDS:

CUDC-101; EGFR; HDAC; anaplastic thyroid cancer; quantitative high-throughput screening

PMID:
25940539
PMCID:
PMC4496203
DOI:
10.18632/oncotarget.3268
[Indexed for MEDLINE]
Free PMC Article

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