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,EZH2,表觀遺傳,EGFR,BRG1,

,EZH2,表觀遺傳,EGFR,BRG1,

2015年2月3日訊 /生物谷BIOON/ --近日,來自美國波士頓兒童醫院的科學家們在國際期刊Nature發表了他們的最新研究成果,他們發現抑制甲基轉移酶EZH2對應用化療藥物治療EGFR和BRG1突變與非突變非小細胞肺癌具有不同影響。
 
非小細胞肺癌是世界范圍內導致癌癥致死的主要殺手,應用拓撲異構酶II抑制劑依托泊苷只對一小部分患有非小細胞肺癌的病人具有良好療效,因此,改變藥物作用靶點正成為藥物治療該疾病的主要問題。研究證明EZH2能與PRC2共同作用對H3K27進行三甲基化,起到基因沉默的作用,因此甲基轉移酶EZH2成為一個非常具有應用前景的潛在作用靶點。
 
Christine M. Fillmore等人發現抑制EZH2對應用拓撲異構酶II抑制劑治療EGFR和BRG1突變與非突變非小細胞肺癌具有不同影響。在BRG1失活的腫瘤細胞中,抑制EZH2會影響細胞周期導致腫瘤細胞的凋亡以及對拓撲異構酶II抑制劑的敏感性增加,同時EGFR功能獲得型突變的腫瘤細胞對抑制EZH2以及拓撲異構酶II抑制劑的敏感性都增加。而在野生型EGFR和BRG1腫瘤細胞中,抑制EZH2會上調BRG1表達導致對拓撲異構酶II抑制劑的抵抗。
 
綜上所述,該文章發現抑制EZH2對應用化療藥物治療EGFR和BRG1突變與非突變非小細胞肺癌具有不同影響,這些發現表明可根據非小細胞肺癌不同基因背景設計針對性藥物治療癌癥,或可成為非小細胞肺癌患者的福音。(生物谷Bioon.com)
 
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,EZH2,表觀遺傳,EGFR,BRG1,
 
doi:10.1038/nature14122
 
EZH2 inhibition sensitizes BRG1 and EGFR mutant lung tumours to TopoII inhibitors
 
Christine M. Fillmore,1, 2, 3, Chunxiao Xu,4, 5, Pooja T. Desai,1, Joanne M. Berry,1, Samuel P. Rowbotham,1, 2, 3, Yi-Jang Lin,2, Haikuo Zhang,4, 5, Victor E. Marquez,6, Peter S. Hammerman,4, Kwok-Kin Wong4, 5, & Carla F. Kim1, 2, 3,
 
Non-small-cell lung cancer is the leading cause of cancer-related death worldwide1. Chemotherapies such as the topoisomerase II (TopoII) inhibitor etoposide effectively reduce disease in a minority of patients with this cancer2, 3; therefore, alternative drug targets, including epigenetic enzymes, are under consideration for therapeutic intervention4. A promising potential epigenetic target is the methyltransferase EZH2, which in the context of the polycomb repressive complex 2 (PRC2) is well known to tri-methylate histone H3 at lysine 27 (H3K27me3) and elicit gene silencing5. Here we demonstrate that EZH2 inhibition has differential effects on the TopoII inhibitor response of non-small-cell lung cancers in vitro and in vivo. EGFR and BRG1 mutations are genetic biomarkers that predict enhanced sensitivity to TopoII inhibitor in response to EZH2 inhibition. BRG1 loss-of-function mutant tumours respond to EZH2 inhibition with increased S phase, anaphase bridging, apoptosis and TopoII inhibitor sensitivity. Conversely, EGFR and BRG1 wild-type tumours upregulate BRG1 in response to EZH2 inhibition and ultimately become more resistant to TopoII inhibitor. EGFR gain-of-function mutant tumours are also sensitive to dual EZH2 inhibition and TopoII inhibitor, because of genetic antagonism between EGFR and BRG1. These findings suggest an opportunity for precision medicine in the genetically complex disease of non-small-cell lung cancer.
 
 

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