Nature: new progress of individualized medical treatment

February 3, 2015 / biourn / - recently, scientists from Boston Children's Hospital published their latest research results in the international journal Nature They found that inhibition of methyltransferase EZH2 had different effects on the treatment of EGFR and BRG1 mutant and non mutant non-small cell lung cancer with chemotherapy drugs Non-small cell lung cancer (NSCLC) is the main killer of cancer death in the world Etoposide, an inhibitor of topoisomerase II, has good curative effect on a small number of patients with NSCLC Therefore, changing the target of drug action is becoming the main problem of drug treatment It has been proved that EZH2 and PRC2 can work together to trimethyl H3K27 and play a role of gene silencing Therefore, EZH2, a methyltransferase, has become a potential target of application Christine M Fillmore et al Found that inhibition of EZH2 had different effects on the treatment of EGFR and BRG1 mutant and non mutant NSCLC with topoisomerase II inhibitors In BRG1 inactivated tumor cells, inhibition of EZH2 can affect cell cycle, leading to apoptosis of tumor cells and increased sensitivity to topoisomerase II inhibitors At the same time, tumor cells with EGFR function acquired mutations have increased sensitivity to inhibition of EZH2 and topoisomerase II inhibitors However, in wild-type EGFR and BRG1 tumor cells, inhibition of EZH2 upregulated BRG1 expression, leading to resistance to topoisomerase II inhibitors To sum up, this paper found that inhibition of EZH2 has different effects on the treatment of EGFR and BRG1 mutation and non mutation NSCLC with chemotherapy drugs These findings indicate that targeted drugs can be designed according to different gene backgrounds of NSCLC, or it can be a good news for NSCLC patients This article is the original compilation of Biovalley, welcome to reprint! Please indicate the source of the reprint and attach the original link Thank you!
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