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Inhibition of HDACs-EphA2 Signaling Axis with WW437 Demonstrates Promising Preclinical Antitumor Activity in Breast Cancer.

Abstract
Histone deacetylase inhibitors (HDACi) are small molecules targeting epigenetic enzymes approved for hematologic neoplasms, which have also demonstrated clinical activities in solid tumors. In our present study, we screened our internal compound library and discovered a novel HDACi, WW437, with potent anti-breast cancer ability in vitro and in vivo. WW437 significantly inhibited phosphorylated EphA2 and EphA2 expression. Further study demonstrated WW437 blocked HDACs-EphA2 signaling axis in breast cancer. In parallel, we found that EphA2 expression positively correlates with breast cancer progression; and combined use of WW437 and an EphA2 inhibitor (ALW-II-41-27) exerted more remarkable effect on breast cancer growth than either drug alone. Our findings suggested inhibition of HDACs-EphA2 signaling axis with WW437 alone or in combination with other agents may be a promising therapeutic strategy for advanced breast cancer.
AuthorsTao Zhang, Jingjie Li, Xiaojun Ma, Yang Yang, Wei Sun, Wangrui Jin, Lei Wang, Yuan He, Feifei Yang, Zhengfang Yi, Yingqi Hua, Mingyao Liu, Yihua Chen, Zhengdong Cai
JournalEBioMedicine (EBioMedicine) Vol. 31 Pg. 276-286 (May 2018) ISSN: 2352-3964 [Electronic] Netherlands
PMID29759486 (Publication Type: Journal Article)
CopyrightCopyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.
Chemical References
  • Antineoplastic Agents
  • EPHA2 protein, human
  • Ephrin-A2
  • Histone Deacetylase Inhibitors
  • Neoplasm Proteins
  • Receptor, EphA2
Topics
  • Antineoplastic Agents (pharmacology)
  • Breast Neoplasms (drug therapy, metabolism, pathology)
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Ephrin-A2 (biosynthesis)
  • Female
  • Gene Expression Regulation, Neoplastic (drug effects)
  • Histone Deacetylase Inhibitors (pharmacology)
  • Humans
  • Neoplasm Proteins (biosynthesis)
  • Receptor, EphA2
  • Signal Transduction (drug effects)

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