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Combined LIM kinase 1 and p21-Activated kinase 4 inhibitor treatment exhibits potent preclinical antitumor efficacy in breast cancer.
Cancer Letters ( IF 9.1 ) Pub Date : 2020-08-21 , DOI: 10.1016/j.canlet.2020.08.006
Chen-Chen Zhao 1 , Meng-Na Zhan 2 , Wan-Ting Liu 1 , Yang Jiao 1 , Yi-Yin Zhang 1 , Yu Lei 1 , Teng-Teng Zhang 1 , Cong-Jun Zhang 1 , Ying-Ying Du 1 , Kang-Sheng Gu 1 , Wei Wei 1
Affiliation  

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.



中文翻译:

LIM激酶1和p21激活的激酶4抑制剂的联合治疗在乳腺癌中表现出有效的临床前抗肿瘤功效。

LIM激酶1(LIMK1)和p21激活的激酶4(PAK4)在乳腺癌中通常过表达,这会导致侵袭性的癌症表型和不良的临床结果。除了在调节细胞分裂,增殖和侵袭中的明确作用外,这两种激酶还通过磷酸化雌激素受体α(ERα)促进MAPK途径的活化并引起内分泌抵抗。PAK4特异性磷酸化LIMK1及其功能伙伴,表明在过度表达PAK4和/或LIMK1的癌症中抑制这两种激酶的可能价值。在这里,我们首次评估了LIMK1抑制剂LIMKi 3和PAK4抑制剂PF-3758309联合在临床前乳腺癌模型中的影响。LIMK1和PAK4的药理抑制作用协同降低了多种癌细胞的存活,在管腔和富含HER2的模型中显示出特定的功效,并在BT474异种移植模型中抑制发育和ERα驱动的信号。计算机分析表明,依赖LIMK1的细胞系最容易受到PAK4抑制的影响。LIMK1和PAK4双重靶向治疗可能是成功的乳腺癌治疗策略,在管腔和富含HER2的肿瘤亚型中具有独特的功效。

更新日期:2020-08-21
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