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Combined LIM kinase 1 and p21-Activated kinase 4 inhibitor treatment exhibits potent preclinical antitumor efficacy in breast cancer.

Authors
  • Zhao, Chen-Chen1
  • Zhan, Meng-Na2
  • Liu, Wan-Ting1
  • Jiao, Yang1
  • Zhang, Yi-Yin1
  • Lei, Yu1
  • Zhang, Teng-Teng1
  • Zhang, Cong-Jun1
  • Du, Ying-Ying1
  • Gu, Kang-Sheng3
  • Wei, Wei4
  • 1 Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui Province, China. , (China)
  • 2 Department of Pathology, Zhong-Shan Hospital Affiliated to Fudan University, Shanghai, 200023, China. , (China)
  • 3 Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui Province, China. Electronic address: [email protected] , (China)
  • 4 Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui Province, China. Electronic address: [email protected] , (China)
Type
Published Article
Journal
Cancer letters
Publication Date
Aug 21, 2020
Volume
493
Pages
120–127
Identifiers
DOI: 10.1016/j.canlet.2020.08.006
PMID: 32829006
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

LIM kinase 1 (LIMK1) and p21-activated kinase 4 (PAK4) are often over-expressed in breast tumors, which causes aggressive cancer phenotypes and unfavorable clinical outcomes. In addition to the well-defined role in regulating cell division, proliferation and invasion, the two kinases promote activation of the MAPK pathway and cause endocrine resistance through phosphorylating estrogen receptor alpha (ERα). PAK4 specifically phosphorylates LIMK1 and its functional partners, indicating possible value of suppressing both kinases in cancers that over-express PAK4 and/or LIMK1. Here, for the first time, we assessed the impact of combining LIMK1 inhibitor LIMKi 3 and PAK4 inhibitor PF-3758309 in preclinical breast cancer models. LIMK1 and PAK4 pharmacological inhibition synergistically reduced the survival of various cancer cell lines, exhibiting specific efficacy in luminal and HER2-enriched models, and suppressed development and ERα-driven signals in a BT474 xenograft model. In silico analysis demonstrated the cell lines with reliance on LIMK1 were the most prone to be susceptible to PAK4 inhibition. Double LIMK1 and PAK4 targeting therapy can be a successful therapeutic strategy for breast cancer, with a unique efficiency in the subtypes of luminal and HER2-enriched tumors. Copyright © 2020 Elsevier B.V. All rights reserved.

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