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

Drug Repurposing

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.

Authors

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; Smallridge, Robert C; Li, Zhuyin; Shen, Min; Kebebew, Electron;

Keywords

  • Animals
  • Antineoplastic Agents/ pharmacology
  • Antineoplastic Agents/ therapeutic use
  • Apoptosis/ drug effects
  • Carcinoma/ drug therapy
  • Carcinoma/ genetics
  • Carcinoma/ secondary
  • Cell Cycle/ drug effects
  • Cell Line, Tumor
  • DNA, Neoplasm/ genetics
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation, Neoplastic/ drug effects
  • High-Throughput Screening Assays
  • Histone Deacetylase Inhibitors/ pharmacology
  • Histone Deacetylase Inhibitors/ therapeutic use
  • Humans
  • Hydroxamic Acids/ pharmacology
  • Hydroxamic Acids/ therapeutic use
  • Mice
  • Molecular Targeted Therapy
  • Mutation
  • Neoplasm Proteins/ antagonists & inhibitors
  • Neoplasm Proteins/ biosynthesis
  • Neoplasm Proteins/ genetics
  • Protein Kinase Inhibitors/ pharmacology
  • Protein Kinase Inhibitors/ therapeutic use
  • Quinazolines/ pharmacology
  • Quinazolines/ therapeutic use
  • Receptor, ErbB-2/ antagonists & inhibitors
  • Small Molecule Libraries
  • Thyroid Neoplasms/ drug therapy
  • Thyroid Neoplasms/ genetics
  • Thyroid Neoplasms/ pathology
  • Xenograft Model Antitumor Assays

External Links