title: EZH2 inhibition sensitizes BRG1 and EGFR mutant lung tumours to TopoII inhibitors.
abstract: Non-small-cell lung cancer is the leading cause of cancer-related death worldwide. Chemotherapies such as the topoisomerase II (TopoII) inhibitor etoposide effectively reduce disease in a minority of patients with this cancer; therefore, alternative drug targets, including epigenetic enzymes, are under consideration for therapeutic intervention. 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 silencing. 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.
authors: 1] Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts 02115, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.
authors: Christine M
authors: CM
authors: Fillmore
authors: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors: Chunxiao
authors: C
authors: Xu
authors: Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
authors: Pooja T
authors: PT
authors: Desai
authors: Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
authors: Joanne M
authors: JM
authors: Berry
authors: 1] Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts 02115, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.
authors: Samuel P
authors: SP
authors: Rowbotham
authors: Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Yi-Jang
authors: YJ
authors: Lin
authors: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors: Haikuo
authors: H
authors: Zhang
authors: Chemical Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, USA.
authors: Victor E
authors: VE
authors: Marquez
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors: Peter S
authors: PS
authors: Hammerman
authors: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors: Kwok-Kin
authors: KK
authors: Wong
authors: 1] Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts 02115, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.
authors: Carla F
authors: CF
authors: Kim
mesh_terms: D000705:Anaphase / Q000187:drug effects; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004265:DNA Helicases / Q000235:genetics*; D000071221:Enhancer of Zeste Homolog 2 Protein; D005047:Etoposide / Q000494:pharmacology / Q000627:therapeutic use; D018773:Genes, erbB-1 / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D051379:Mice; D058990:Molecular Targeted Therapy; D009687:Nuclear Proteins / Q000235:genetics*; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors*; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D014157:Transcription Factors / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D009687:Nuclear Proteins; D059005:Topoisomerase II Inhibitors; D014157:Transcription Factors; D005047:Etoposide; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; C084108:SMARCA4 protein, human; D004265:DNA Helicases
references: PLoS Genet. 2008;4(7):e1000129
references: 18636107
references: Mol Cancer Ther. 2008 Jul;7(7):1923-30
references: 18606719
references: Oncogene. 2008 Jul 31;27(33):4615-24
references: 18391978
references: Nat Med. 2008 Aug;14(8):822-7
references: 18641660
references: Cancer Res. 2008 Sep 1;68(17):6913-21
references: 18757405
references: Mutat Res. 2008 Dec 1;647(1-2):21-9
references: 18723033
references: J Transl Med. 2008;6:69
references: 18992152
references: Nucleic Acids Res. 2009 Feb;37(3):738-48
references: 19042970
references: Cancer Res. 2010 Jan 15;70(2):440-6
references: 20068163
references: Cell Stem Cell. 2010 Jul 2;7(1):127-33
references: 20621056
references: Cancer Cell. 2010 Oct 19;18(4):316-28
references: 20951942
references: Cell Res. 2011 Mar;21(3):396-420
references: 21358755
references: CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90
references: 21296855
references: Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21737-42
references: 21098263
references: Cell Stem Cell. 2011 Sep 2;9(3):272-81
references: 21885022
references: Nat Rev Cancer. 2011 Oct;11(10):726-34
references: 21941284
references: Br J Cancer. 2004 Jul 19;91(2):355-8
references: 15188009
references: Adv Enzyme Regul. 1984;22:27-55
references: 6382953
references: Stat Med. 1990 Jul;9(7):811-8
references: 2218183
references: Bioinformatics. 2005 May 1;21(9):2067-75
references: 15657102
references: Carcinogenesis. 2011 Oct;32(10):1525-32
references: 21798853
references: Nature. 2012 Mar 29;483(7391):603-7
references: 22460905
references: Lung Cancer. 2012 Jul;77(1):89-96
references: 22418243
references: Cell. 2005 May 6;121(3):335-48
references: 15882617
references: Cancer Res. 2005 Nov 15;65(22):10280-8
references: 16288016
references: Genes Dev. 2006 Feb 1;20(3):282-96
references: 16452502
references: Cancer Cell. 2006 Jun;9(6):485-95
references: 16730237
references: Pharmacol Rev. 2006 Sep;58(3):621-81
references: 16968952
references: J Clin Invest. 2006 Oct;116(10):2695-706
references: 16906227
references: BMC Genomics. 2006;7:289
references: 17096850
references: Neoplasia. 2007 Feb;9(2):166-80
references: 17356713
references: Mol Cancer Ther. 2007 Mar;6(3):820-32
references: 17339364
references: Genes Dev. 2007 May 1;21(9):1050-63
references: 17437993
references: BMC Genomics. 2007;8:140
references: 17540040
references: J Biol Chem. 2008 Jan 11;283(2):1146-55
references: 18003620
references: PLoS One. 2008;3(2):e1651
references: 18297132
references: Hum Mutat. 2008 May;29(5):617-22
references: 18386774
references: J Natl Compr Canc Netw. 2012 Jul 1;10(7):847-56
references: 22773800
references: Nature. 2012 Sep 6;489(7414):57-74
references: 22955616
references: Cell. 2012 Sep 14;150(6):1107-20
references: 22980975
references: Nature. 2012 Dec 6;492(7427):108-12
references: 23051747
references: Cancer Sci. 2013 Feb;104(2):266-73
references: 23163725
references: Nature. 2013 May 30;497(7451):624-7
references: 23698369
references: Cancer Res. 2013 Sep 1;73(17):5508-18
references: 23872584
references: Nature. 2014 Jul 31;511(7511):543-50
references: 25079552
references: Proc Natl Acad Sci U S A. 2001 Jan 2;98(1):31-6
references: 11134512
references: Cancer Res. 2001 Oct 15;61(20):7388-93
references: 11606367
references: Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13784-9
references: 11707590
references: Nat Med. 2002 Aug;8(8):816-24
references: 12118244
references: Cancer Res. 2002 Sep 1;62(17):4963-7
references: 12208747
references: Biostatistics. 2003 Apr;4(2):249-64
references: 12925520