Oncotarget

Research Papers:

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

Lisa Zhang, Yaqin Zhang, Amit Mehta, Myriem Boufraqech, Sean Davis, Jing Wang, Ze Tian, Zhiya Yu, Matthew B. Boxer, Jeffrey A. Kiefer, John A. Copland, Robert C. Smallridge, Zhuyin Li, Min Shen and Electron Kebebew _

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Oncotarget. 2015; 6:9073-9085. https://doi.org/10.18632/oncotarget.3268

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Abstract

Lisa Zhang1, Yaqin Zhang2, Amit Mehta1,3, Myriem Boufraqech1, Sean Davis4, Jing Wang5, Ze Tian5, Zhiya Yu6, Matthew B. Boxer2, Jeffrey A. Kiefer7, John A. Copland8, Robert C. Smallridge8,9, Zhuyin Li2, Min Shen2, Electron Kebebew1

1Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

2Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA

3Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA

4Cancer Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

5Curis, Inc., Translational Science MA, USA

6Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

7Division of Information Sciences, Translational Genomics Research Institute, Phoenix, AZ, USA

8Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA

9Endocrinology Division, Internal Medicine Department, Mayo Clinic, Jacksonville, FL, USA

Correspondence to:

Electron Kebebew, e-mail: kebebewe@mail.nih.gov

Keywords: CUDC-101, anaplastic thyroid cancer, quantitative high-throughput screening, EGFR, HDAC

Received: January 26, 2015     Accepted: January 31, 2015     Published: April 13, 2015

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 higher 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 nuclear expression. Our findings provide a preclinical basis to evaluate CUDC-101 therapy in ATC.


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