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Targeting PKCι-PAK1 signaling pathways in EGFR and KRAS mutant adenocarcinoma and lung squamous cell carcinoma.
Cell Communication and Signaling ( IF 8.2 ) Pub Date : 2019-10-28 , DOI: 10.1186/s12964-019-0446-z
Masaoki Ito 1, 2, 3 , Carles Codony-Servat 1, 4 , Jordi Codony-Servat 1 , David Lligé 2 , Imane Chaib 2 , Xiaoyan Sun 5 , Jing Miao 5 , Rongwei Sun 5 , Xueting Cai 5 , Alberto Verlicchi 1, 6 , Morihito Okada 3 , Miguel Angel Molina-Vila 1 , Niki Karachaliou 1 , Peng Cao 5, 7, 8 , Rafael Rosell 2, 9, 10
Affiliation  

INTRODUCTION p21-activated kinase 1 (PAK1) stimulates growth and metastasis in non-small cell lung cancer (NSCLC). Protein kinase C iota (PKCι) is an enzyme highly expressed in NSCLC, regulating PAK1 signaling. In the present study we explored whether the PKCι-PAK1 signaling pathway approach can be an efficient target in different types of NSCLC cell and mouse models. METHODS The effect of IPA-3 (PAK1 inhibitor) plus auranofin (PKCι inhibitor) combination was evaluated by cell viability assay, colony formation and western blotting assay, using three types of NSCLC cell lines: EGFR or KRAS mutant adenocarcinoma and squamous cell carcinoma with PAK1 amplification. In addition, for clinical availability, screening for new PAK1 inhibitors was carried out and the compound OTSSP167 was evaluated in combination with auranofin in cell and mice models. RESULTS The combination of IPA-3 or OTSSP167 plus auranofin showed high synergism for inhibiting cell viability and colony formation in three cell lines. Mechanistic characterization revealed that this drug combination abrogated expression and activation of membrane receptors and downstream signaling proteins crucial in lung cancer: EGFR, MET, PAK1, PKCι, ERK1/2, AKT, YAP1 and mTOR. A nude mouse xenograft assay demonstrated that this drug combination strongly suppressed tumor volume compared with single drug treatment. CONCLUSIONS Combination of IPA-3 or OTSSP167 and auranofin was highly synergistic in EGFR or KRAS mutant adenocarcinoma and squamous cell carcinoma cell lines and decreased tumor volume in mice models. It is of interest to further test the targeting of PKCι-PAK1 signaling pathways in EGFR mutant, KRAS mutant and squamous NSCLC patients.

中文翻译:

在EGFR和KRAS突变腺癌和肺鳞状细胞癌中靶向PKC1-PAK1信号传导途径。

简介p21激活激酶1(PAK1)刺激非小细胞肺癌(NSCLC)的生长和转移。蛋白激酶C ota(PKC 1)是在NSCLC中高度表达的酶,其调节PAK1信号传导。在本研究中,我们探索了PKC1-PAK1信号通路途径是否可以成为不同类型的NSCLC细胞和小鼠模型中的有效靶标。方法使用三种类型的NSCLC细胞系,通过EGFR或KRAS突变型腺癌和鳞状上皮细胞癌,通过细胞活力测定,集落形成和蛋白质印迹测定来评估IPA-3(PAK1抑制剂)和金诺芬(PKC1抑制剂)联合使用的效果。 PAK1扩增。另外,为了临床上的方便,对新的PAK1抑制剂进行了筛选,并在细胞和小鼠模型中与金刚霉素联合评估了化合物OTSSP167。结果IPA-3或OTSSP167加上金诺芬的组合显示出在抑制三种细胞系中细胞活力和集落形成方面的高协同作用。机理表征表明,该药物组合消除了对肺癌至关重要的膜受体和下游信号蛋白的表达和激活:EGFR,MET,PAK1,PKC1,ERK1 / 2,AKT,YAP1和mTOR。裸鼠异种移植测定法表明,与单一药物治疗相比,该药物组合可显着抑制肿瘤体积。结论IPA-3或OTSSP167与金诺芬的组合在EGFR或KRAS突变腺癌和鳞状细胞癌细胞系中具有高度协同作用,并在小鼠模型中降低了肿瘤体积。感兴趣的是进一步测试EGFR突变体中PKC1-PAK1信号通路的靶向,
更新日期:2019-11-28
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