title: Efficacy of BET bromodomain inhibition in Kras-mutant non-small cell lung cancer.
abstract: OBJECTIVE
  Amplification of MYC is one of the most common genetic alterations in lung cancer, contributing to a myriad of phenotypes associated with growth, invasion, and drug resistance. Murine genetics has established both the centrality of somatic alterations of Kras in lung cancer, as well as the dependency of mutant Kras tumors on MYC function. Unfortunately, drug-like small-molecule inhibitors of KRAS and MYC have yet to be realized. The recent discovery, in hematologic malignancies, that bromodomain and extra-terminal (BET) bromodomain inhibition impairs MYC expression and MYC transcriptional function established the rationale of targeting KRAS-driven non-small cell lung cancer (NSCLC) with BET inhibition.
  
  
  METHODS
  We performed functional assays to evaluate the effects of JQ1 in genetically defined NSCLC cell lines harboring KRAS and/or LKB1 mutations. Furthermore, we evaluated JQ1 in transgenic mouse lung cancer models expressing mutant kras or concurrent mutant kras and lkb1. Effects of bromodomain inhibition on transcriptional pathways were explored and validated by expression analysis.
  
  
  RESULTS
  Although JQ1 is broadly active in NSCLC cells, activity of JQ1 in mutant KRAS NSCLC is abrogated by concurrent alteration or genetic knockdown of LKB1. In sensitive NSCLC models, JQ1 treatment results in the coordinate downregulation of the MYC-dependent transcriptional program. We found that JQ1 treatment produces significant tumor regression in mutant kras mice. As predicted, tumors from mutant kras and lkb1 mice did not respond to JQ1.
  
  
  CONCLUSIONS
  Bromodomain inhibition comprises a promising therapeutic strategy for KRAS-mutant NSCLC with wild-type LKB1, via inhibition of MYC function. Clinical studies of BET bromodomain inhibitors in aggressive NSCLC will be actively pursued. Clin Cancer Res; 19(22); 6183-92. ©2013 AACR.
authors.affiliation: Authors' Affiliations: Department of Molecular Pharmacology and Therapeutics, Oncology Research Institute, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois; Departments of Medical Oncology and Radiation Oncology; Belfer Institute for Applied Cancer Science; Ludwig Center at Dana-Farber/Harvard Cancer Center; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute; Department of Medicine, Brigham and Women's Hospital; Department of Medicine, Harvard Medical School, Boston, Massachusetts; Departament de Fisiologia, Facultat de Farmàcia, Universitat de València, Valencia, Spain; and Department of Pediatrics, Columbia University Medical Center, New York, New York.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimamura
authors.forename: Zhao
authors.initials: Z
authors.lastname: Chen
authors.forename: Margaret
authors.initials: M
authors.lastname: Soucheray
authors.forename: Julian
authors.initials: J
authors.lastname: Carretero
authors.forename: Eiki
authors.initials: E
authors.lastname: Kikuchi
authors.forename: Jeremy H
authors.initials: JH
authors.lastname: Tchaicha
authors.forename: Yandi
authors.initials: Y
authors.lastname: Gao
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Cheng
authors.forename: Travis J
authors.initials: TJ
authors.lastname: Cohoon
authors.forename: Jun
authors.initials: J
authors.lastname: Qi
authors.forename: Esra
authors.initials: E
authors.lastname: Akbay
authors.forename: Alec C
authors.initials: AC
authors.lastname: Kimmelman
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001381:Azepines / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics; D014230:Triazoles / Q000494:pharmacology*; D000092468:Bromodomain Containing Proteins
chemical_list: D055372:AMP-Activated Protein Kinases; D001381:Azepines; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D016271:Proto-Oncogene Proteins c-myc; D016283:Proto-Oncogene Proteins p21(ras); D034741:RNA, Small Interfering; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C486694:Brd4 protein, mouse; D000092468:Bromodomain Containing Proteins; C491654:Stk11 protein, mouse; C495971:Hras protein, mouse
references.citation: Nat Rev Cancer. 2002 Oct;2(10):764-76
references.pmid: 12360279
references.citation: Cell. 2011 Sep 16;146(6):904-17
references.pmid: 21889194
references.citation: Cancer Discov. 2013 Mar;3(3):308-23
references.pmid: 23430699
references.citation: Nature. 2008 Oct 2;455(7213):679-83
references.pmid: 18716624
references.citation: Nat Rev Cancer. 2003 Jun;3(6):459-65
references.pmid: 12778136
references.citation: Nature. 2007 Aug 16;448(7155):807-10
references.pmid: 17676035
references.citation: Nature. 2001 Apr 26;410(6832):1111-6
references.pmid: 11323676
references.citation: Oncogene. 2005 Jan 13;24(3):520-4
references.pmid: 15516975
references.citation: Nat Rev Cancer. 2002 Oct;2(10):740-9
references.pmid: 12360277
references.citation: Nature. 2010 Feb 18;463(7283):899-905
references.pmid: 20164920
references.citation: Nat Cell Biol. 2004 Apr;6(4):308-18
references.pmid: 15048125
references.citation: Cell. 2009 May 29;137(5):821-34
references.pmid: 19490892
references.citation: Cell. 2009 May 29;137(5):835-48
references.pmid: 19490893
references.citation: Nat Med. 2008 Dec;14(12):1351-6
references.pmid: 19029981
references.citation: Cancer Cell. 2010 Jun 15;17(6):547-59
references.pmid: 20541700
references.citation: Clin Cancer Res. 2012 Oct 15;18(20):5773-9
references.pmid: 22896655
references.citation: Cancer Res. 2008 Jul 15;68(14):5827-38
references.pmid: 18632637
references.citation: Nat Rev Cancer. 2011 Oct 13;11(11):761-74
references.pmid: 21993244
references.citation: Cancer Cell. 2009 Jun 2;15(6):489-500
references.pmid: 19477428
references.citation: Nucleic Acids Res. 2001 Jan 15;29(2):397-406
references.pmid: 11139609
references.citation: Nature. 2012 Mar 18;483(7391):613-7
references.pmid: 22425996
references.citation: Cell. 2012 Sep 28;151(1):56-67
references.pmid: 23021215
references.citation: Nature. 2011 Aug 03;478(7370):524-8
references.pmid: 21814200
references.citation: Nature. 2009 Nov 5;462(7269):108-12
references.pmid: 19847166
references.citation: Nature. 2010 Dec 23;468(7327):1067-73
references.pmid: 20871596
references.citation: Genes Dev. 2013 Mar 1;27(5):504-13
references.pmid: 23475959
references.citation: Proc Natl Acad Sci U S A. 2012 Nov 20;109(47):19408-13
references.pmid: 23129625
references.citation: Genes Dev. 2000 Oct 1;14(19):2501-14
references.pmid: 11018017