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 III Copland, Robert Christian Smallridge, Zhuyin Li, Min Shen, Electron Kebebew

Research output: Contribution to journalArticle

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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 IC<inf>50</inf> 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.

Original languageEnglish (US)
Pages (from-to)9073-9085
Number of pages13
JournalOncotarget
Volume6
Issue number11
StatePublished - 2015

Fingerprint

Histone Deacetylases
Neoplasm Metastasis
Growth
Neoplasms
Cadherins
Histones
Pharmaceutical Preparations
Cell Line
Catenins
Histone Deacetylase Inhibitors
7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide
Anaplastic Thyroid Carcinoma
Vimentin
Acetylation
Caspases
Cell Cycle Checkpoints
Inhibitory Concentration 50
Cell Death
Cell Proliferation
Apoptosis

Keywords

  • Anaplastic thyroid cancer
  • CUDC-101
  • EGFR
  • HDAC
  • Quantitative high-throughput screening

ASJC Scopus subject areas

  • Oncology

Cite this

Zhang, L., Zhang, Y., Mehta, A., Boufraqech, M., Davis, S., Wang, J., ... Kebebew, E. (2015). Dual inhibition of HDAC and EGFR signaling with CUDC-101 induces potent suppression of tumor growth and metastasis in anaplastic thyroid cancer. Oncotarget, 6(11), 9073-9085.

Dual inhibition of HDAC and EGFR signaling with CUDC-101 induces potent suppression of tumor growth and metastasis in anaplastic thyroid cancer. / Zhang, Lisa; Zhang, Yaqin; Mehta, Amit; Boufraqech, Myriem; Davis, Sean; Wang, Jing; Tian, Ze; Yu, Zhiya; Boxer, Matthew B.; Kiefer, Jeffrey A.; Copland, John A III; Smallridge, Robert Christian; Li, Zhuyin; Shen, Min; Kebebew, Electron.

In: Oncotarget, Vol. 6, No. 11, 2015, p. 9073-9085.

Research output: Contribution to journalArticle

Zhang, L, Zhang, Y, Mehta, A, Boufraqech, M, Davis, S, Wang, J, Tian, Z, Yu, Z, Boxer, MB, Kiefer, JA, Copland, JAIII, Smallridge, RC, Li, Z, Shen, M & Kebebew, E 2015, 'Dual inhibition of HDAC and EGFR signaling with CUDC-101 induces potent suppression of tumor growth and metastasis in anaplastic thyroid cancer', Oncotarget, vol. 6, no. 11, pp. 9073-9085.
Zhang, Lisa ; Zhang, Yaqin ; Mehta, Amit ; Boufraqech, Myriem ; Davis, Sean ; Wang, Jing ; Tian, Ze ; Yu, Zhiya ; Boxer, Matthew B. ; Kiefer, Jeffrey A. ; Copland, John A III ; Smallridge, Robert Christian ; Li, Zhuyin ; Shen, Min ; Kebebew, Electron. / Dual inhibition of HDAC and EGFR signaling with CUDC-101 induces potent suppression of tumor growth and metastasis in anaplastic thyroid cancer. In: Oncotarget. 2015 ; Vol. 6, No. 11. pp. 9073-9085.
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