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Gemcitabine and Chk1 Inhibitor AZD7762 Synergistically Suppress the Growth of Lkb1-Deficient Lung Adenocarcinoma
Liu, Yan1; Li, Yuyang2; Wang, Xiaoen1; Liu, Feiyang3; Gao, Peng1; Quinn, Max M.1; Li, Fei1; Merlino, Ashley A.1; Benes, Cyril4; Liu, Qingsong3; Gray, Nathanael S.5; Wong, Kwok-Kin6
2017-09-15
发表期刊CANCER RESEARCH
卷号77期号:18页码:5068-5076
摘要Cells lacking the tumor suppressor gene LKB1/STK11 alter their metabolism to match the demands of accelerated growth, leaving them highly vulnerable to stress. However, targeted therapy for LKB1-deficient cancers has yet to be reported. In both Kras/p53/Lkb1 cell lines and a genetically engineered mouse model of Kras/p53/Lkb1-induced lung cancer, much higher rates of DNA damage occur, resulting in increased dependence on Chk1 checkpoint function. Here we demon-strate that short-term treatment with the Chk1 inhibitor AZD7762 reduces metabolism in pembrolizumab tumors, synergizing with the DNA-damaging drug gemcitabine to reduce tumor size in these models. Our results offer preclinical proof of concept for use of a Chk1 inhibitor to safely enhance the efficacy of gemcitabine, particularly in aggressive KRAS-driven LKB1-deficient lung adenocarcinomas. (C)2017 AACR.
文章类型Article
WOS标题词Science & Technology ; Life Sciences & Biomedicine
资助者National Cancer Institute(R01 CA195740 ; National Cancer Institute(R01 CA195740 ; Stand Up To Cancer-American Cancer Society Lung Cancer Dream Team Translational Research Grant(SU2C-AACR-DT17-15) ; Stand Up To Cancer-American Cancer Society Lung Cancer Dream Team Translational Research Grant(SU2C-AACR-DT17-15) ; CA163896 ; CA163896 ; CA166480 ; CA166480 ; CA122794 ; CA122794 ; CA140594) ; CA140594) ; National Cancer Institute(R01 CA195740 ; National Cancer Institute(R01 CA195740 ; Stand Up To Cancer-American Cancer Society Lung Cancer Dream Team Translational Research Grant(SU2C-AACR-DT17-15) ; Stand Up To Cancer-American Cancer Society Lung Cancer Dream Team Translational Research Grant(SU2C-AACR-DT17-15) ; CA163896 ; CA163896 ; CA166480 ; CA166480 ; CA122794 ; CA122794 ; CA140594) ; CA140594)
DOI10.1158/0008-5472.CAN-17-0567
关键词[WOS]ADVANCED SOLID TUMORS ; THERAPEUTIC RESPONSE ; DOSE-ESCALATION ; CELL-GROWTH ; PHASE-I ; CANCER ; METABOLISM ; INACTIVATION ; AMPK ; CHECKPOINT
收录类别SCI
语种英语
资助者National Cancer Institute(R01 CA195740 ; National Cancer Institute(R01 CA195740 ; Stand Up To Cancer-American Cancer Society Lung Cancer Dream Team Translational Research Grant(SU2C-AACR-DT17-15) ; Stand Up To Cancer-American Cancer Society Lung Cancer Dream Team Translational Research Grant(SU2C-AACR-DT17-15) ; CA163896 ; CA163896 ; CA166480 ; CA166480 ; CA122794 ; CA122794 ; CA140594) ; CA140594) ; National Cancer Institute(R01 CA195740 ; National Cancer Institute(R01 CA195740 ; Stand Up To Cancer-American Cancer Society Lung Cancer Dream Team Translational Research Grant(SU2C-AACR-DT17-15) ; Stand Up To Cancer-American Cancer Society Lung Cancer Dream Team Translational Research Grant(SU2C-AACR-DT17-15) ; CA163896 ; CA163896 ; CA166480 ; CA166480 ; CA122794 ; CA122794 ; CA140594) ; CA140594)
WOS研究方向Oncology
WOS类目Oncology
WOS记录号WOS:000410945700028
引用统计
被引频次:2[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.hfcas.ac.cn:8080/handle/334002/33680
专题中科院强磁场科学中心
作者单位1.Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA
2.Shandong Univ, Shandong Prov Hosp, Jinan, Shandong, Peoples R China
3.Chinese Acad Sci, High Field Magnet Lab, Hefei, Anhui, Peoples R China
4.Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA
5.Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA
6.NYU, Langone Med Ctr New York, Laura & Isaac Perlmutter Canc Ctr, New York, NY 10016 USA
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Liu, Yan,Li, Yuyang,Wang, Xiaoen,et al. Gemcitabine and Chk1 Inhibitor AZD7762 Synergistically Suppress the Growth of Lkb1-Deficient Lung Adenocarcinoma[J]. CANCER RESEARCH,2017,77(18):5068-5076.
APA Liu, Yan.,Li, Yuyang.,Wang, Xiaoen.,Liu, Feiyang.,Gao, Peng.,...&Wong, Kwok-Kin.(2017).Gemcitabine and Chk1 Inhibitor AZD7762 Synergistically Suppress the Growth of Lkb1-Deficient Lung Adenocarcinoma.CANCER RESEARCH,77(18),5068-5076.
MLA Liu, Yan,et al."Gemcitabine and Chk1 Inhibitor AZD7762 Synergistically Suppress the Growth of Lkb1-Deficient Lung Adenocarcinoma".CANCER RESEARCH 77.18(2017):5068-5076.
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