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Simultaneous inhibition of PI3K alpha and CDK4/6 synergistically suppresses KRAS-mutated non-small cell lung cancer

文献类型：期刊论文

作者Wang, Yuxiang2,3; Li, Xian2; Liu, Xueling2,3; Chen, Yi1,3; Yang, Chunhao4; Tan, Cun4; Wang, Bobo2; Sun, Yiming1,3; Zhang, Xi2; Gao, Yinglei1,3
刊名CANCER BIOLOGY & MEDICINE
出版日期2019-02-01
卷号16期号:1页码:66-+
关键词PI3K alpha CDK4/6 KRAS NSCLC CYH33
ISSN号2095-3941
DOI10.20892/j.issn.2095-3941.2018.0361
通讯作者Ding, Jian(jding@simm.ac.cn) ; Meng, Linghua(lhmeng@simm.ac.cn)
英文摘要Objective: Activating KRAS mutations are the most common drivers in the development of non-small cell lung cancer (NSCLC). However, unsuccess of treatment by direct inhibition of KRAS has been proven. Deregulation of PI3K signaling plays an important role in tumorigenesis and drug resistance in NSCLC. The activity of PI3K alpha-selective inhibition against KRAS-mutated NSCLC remains largely unknown. Methods: Cell proliferation was detected by sulforhodamine B assay. Cell cycle distribution and apoptosis were measured by flow cytometry. Cell signaling was assessed by Western blot and immunohistochemistry. RNA interference was used to down-regulate the expression of cyclin D1. Human NSCLC xenografts were employed to detect therapeutic efficacy in vivo. Results: CYH33 possessed variable activity against a panel of KRAS-mutated NSCLC cell lines. Although CYH33 blocked AKT phosphorylation in all tested cells, Rb phosphorylation decreased in CYH33-sensitive, but not in CYH33-resistant cells, which was consistent with G1 phase arrest in sensitive cells. Combined treatment with the CDK4/6 inhibitor, PD0332991, and CYH33 displayed synergistic activity against the proliferation of both CYH33-sensitive and CYH33-resistant cells, which was accompanied by enhanced G1-phase arrest. Moreover, down-regulation of cyclin D1 sensitized NSCLC cells to CYH33. Reciprocally, CYH33 abrogated the PD0332991-induced up-regulation of cyclin D1 and phosphorylation of AKT in A549 cells. Co-treatment with these two drugs demonstrated synergistic activity against A549 and H23 xenografts, with enhanced inhibition of Rb phosphorylation. Conclusions: Simultaneous inhibition of PI3K alpha and CDK4/6 displayed synergistic activity against KRAS-mutated NSCLC. These data provide a mechanistic rationale for the combination of a PI3K alpha inhibitor and a CDK4/6 inhibitor for the treatment of KRAS-mutated NSCLC.
WOS关键词BREAST-CANCER ; PI3K PATHWAY ; MUTATIONS ; RESISTANCE ; PIK3CA ; EGFR ; REARRANGEMENTS ; COMBINATION ; DERIVATIVES
资助项目Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020218] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020111] ; National Science and Technology Major Project Key New Drug Creation and Manufacturing Program[2018ZX09711002-011-014] ; National Natural Science Foundation of China[81773760] ; Fudan-SIMM Joint Research Program[FU-SIMM20172005]
WOS研究方向Oncology ; Research & Experimental Medicine
语种英语
WOS记录号WOS:000460532200007
出版者CHINESE ANTI-CANCER ASSOC
源URL[http://119.78.100.183/handle/2S10ELR8/290378]  
专题中国科学院上海药物研究所
通讯作者Ding, Jian; Meng, Linghua
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 200120, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Yuxiang,Li, Xian,Liu, Xueling,et al. Simultaneous inhibition of PI3K alpha and CDK4/6 synergistically suppresses KRAS-mutated non-small cell lung cancer[J]. CANCER BIOLOGY & MEDICINE,2019,16(1):66-+.
APA Wang, Yuxiang.,Li, Xian.,Liu, Xueling.,Chen, Yi.,Yang, Chunhao.,...&Meng, Ling-hua.(2019).Simultaneous inhibition of PI3K alpha and CDK4/6 synergistically suppresses KRAS-mutated non-small cell lung cancer.CANCER BIOLOGY & MEDICINE,16(1),66-+.
MLA Wang, Yuxiang,et al."Simultaneous inhibition of PI3K alpha and CDK4/6 synergistically suppresses KRAS-mutated non-small cell lung cancer".CANCER BIOLOGY & MEDICINE 16.1(2019):66-+.

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来源：上海药物研究所

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