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Combined LIM kinase 1 and p21-Activated kinase 4 inhibitor treatment exhibits potent preclinical antitumor efficacy in breast cancer.
Zhao, Chen-Chen; Zhan, Meng-Na; Liu, Wan-Ting; Jiao, Yang; Zhang, Yi-Yin; Lei, Yu; Zhang, Teng-Teng; Zhang, Cong-Jun; Du, Ying-Ying; Gu, Kang-Sheng; Wei, Wei.
Afiliação
  • Zhao CC; Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui Province, China.
  • Zhan MN; Department of Pathology, Zhong-Shan Hospital Affiliated to Fudan University, Shanghai, 200023, China.
  • Liu WT; Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui Province, China.
  • Jiao Y; Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui Province, China.
  • Zhang YY; Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui Province, China.
  • Lei Y; Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui Province, China.
  • Zhang TT; Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui Province, China.
  • Zhang CJ; Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui Province, China.
  • Du YY; Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui Province, China.
  • Gu KS; Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui Province, China. Electronic address: gukangsheng@ahmu.edu.cn.
  • Wei W; Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui Province, China. Electronic address: wwei1213@yeah.net.
Cancer Lett ; 493: 120-127, 2020 11 28.
Article em En | MEDLINE | ID: mdl-32829006
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Pirazóis / Pirróis / Tiazóis / Neoplasias da Mama / Quinases Lim / Quinases Ativadas por p21 Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Pirazóis / Pirróis / Tiazóis / Neoplasias da Mama / Quinases Lim / Quinases Ativadas por p21 Idioma: En Ano de publicação: 2020 Tipo de documento: Article