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    • Inhibition of PI3K Pathway Reduces Invasiveness and Epithelial-to-Mesenchymal Transition in Squamous Lung Cancer Cell Lines Harboring PIK3CA Gene Alterations.

    Molecular cancer therapeutics（2015）SCI 2区

    Univ Parma | Univ Hosp Parma

    Cited 34|Views70
    Abstract
    Abstract A prominent role in the pathogenesis of squamous cell carcinoma of the lung (SQCLC) has been attributed to the aberrant activation of the PI3K signaling pathway, due to amplification or mutations of the p110α subunit of class I phosphatidylinositol 3-kinase (PIK3CA) gene. The aim of our study was to determine whether different genetic alterations of PIK3CA affect the biologic properties of SQCLC and to evaluate the response to specific targeting agents in vitro and in vivo. The effects of NVP-BEZ235, NVP-BKM120, and NVP-BYL719 on two-dimensional/three-dimensional (2D/3D) cellular growth, epithelial-to-mesenchymal transition, and invasiveness were evaluated in E545K or H1047R PIK3CA–mutated SQCLC cells and in newly generated clones carrying PIK3CA alterations, as well as in a xenograft model. PIK3CA mutated/amplified cells showed increased growth rate and enhanced migration and invasiveness, associated with an increased activity of RhoA family proteins and the acquisition of a mesenchymal phenotype. PI3K inhibitors reverted this aggressive phenotype by reducing metalloproteinase production, RhoA activity, and the expression of mesenchymal markers, with the specific PI3K inhibitors NVP-BKM120 and NVP-BYL719 being more effective than the dual PI3K/mTOR inhibitor NVP-BEZ235. A xenograft model of SQCLC confirmed that PIK3CA mutation promotes the acquisition of a mesenchymal phenotype in vivo and proved the efficacy of its specific targeting drug NVP-BYL719 in reducing the growth and the expression of mesenchymal markers in xenotransplanted tumors. These data indicate that PIK3CA mutation/amplification may represent a good predictive feature for the clinical application of specific PI3K inhibitors in SQCLC patients. Mol Cancer Ther; 14(8); 1916–27. ©2015 AACR.
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    PI3K/AKT pathway,Cell Growth
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    【要点】：研究探讨了PI3K信号通路抑制剂对PIK3CA基因变异的鳞状细胞肺癌细胞系的侵袭性和上皮-间质转化（EMT）的影响，发现PI3K抑制剂能显著降低肿瘤细胞的侵袭性和EMT，且特定抑制剂效果更佳。
    

    【方法】：通过在体外和体内评估NVP-BEZ235、NVP-BKM120和NVP-BYL719三种PI3K抑制剂对E545K或H1047R PIK3CA基因变异的鳞状细胞肺癌细胞系的影响，包括二维/三维细胞生长、上皮-间质转化和侵袭性。
    

    【实验】：在E545K或H1047R PIK3CA基因变异的细胞系以及新生的携带PIK3CA变异的克隆中进行实验，并使用人肺癌异种移植模型（xenograft model）。实验结果显示，PI3K抑制剂能逆转肿瘤细胞的侵袭性表型，减少金属基质蛋白酶的产生、RhoA蛋白的活性和间质标记物的表达，其中NVP-BKM120和NVP-BYL719效果优于NVP-BEZ235。在异种移植肿瘤模型中，PIK3CA突变促进了间质表型的获得，且NVP-BYL719能有效减少肿瘤生长和间质标记物的表达。