title: EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer.
abstract: OBJECTIVE
  The EML4-ALK fusion gene has been detected in approximately 7% of Japanese non-small cell lung cancers (NSCLC). We determined the frequency of EML4-ALK in Caucasian NSCLC and in NSCLC cell lines. We also determined whether TAE684, a specific ALK kinase inhibitor, would inhibit the growth of EML4-ALK-containing cell lines in vitro and in vivo.
  
  
  METHODS
  We screened 305 primary NSCLC [both U.S. (n = 138) and Korean (n = 167) patients] and 83 NSCLC cell lines using reverse transcription-PCR and by exon array analyses. We evaluated the efficacy of TAE684 against NSCLC cell lines in vitro and in vivo.
  
  
  RESULTS
  We detected four different variants, including two novel variants, of EML4-ALK using reverse transcription-PCR in 8 of 305 tumors (3%) and 3 of 83 (3.6%) NSCLC cell lines. All EML4-ALK-containing tumors and cell lines were adenocarcinomas. EML4-ALK was detected more frequently in NSCLC patients who were never or light (<10 pack-years) cigarette smokers compared with current/former smokers (6% versus 1%; P = 0.049). TAE684 inhibited the growth of one of three (H3122) EML4-ALK-containing cell lines in vitro and in vivo, inhibited Akt phosphorylation, and caused apoptosis. In another EML4-ALK cell line, DFCI032, TAE684 was ineffective due to coactivation of epidermal growth factor receptor and ERBB2. The combination of TAE684 and CL-387,785 (epidermal growth factor receptor/ERBB2 kinase inhibitor) inhibited growth and Akt phosphorylation and led to apoptosis in the DFCI032 cell line.
  
  
  CONCLUSIONS
  EML4-ALK is found in the minority of NSCLC. ALK kinase inhibitors alone or in combination may nevertheless be clinically effective treatments for NSCLC patients whose tumors contain EML4-ALK.
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, D820A, 44 Binney Street, Boston, MA 02115, USA.
authors.forename: Jussi P
authors.initials: JP
authors.lastname: Koivunen
authors.forename: Craig
authors.initials: C
authors.lastname: Mermel
authors.forename: Kreshnik
authors.initials: K
authors.lastname: Zejnullahu
authors.forename: Carly
authors.initials: C
authors.lastname: Murphy
authors.forename: Eugene
authors.initials: E
authors.lastname: Lifshits
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Holmes
authors.forename: Hwan Geun
authors.initials: HG
authors.lastname: Choi
authors.forename: Jhingook
authors.initials: J
authors.lastname: Kim
authors.forename: Derek
authors.initials: D
authors.lastname: Chiang
authors.forename: Roman
authors.initials: R
authors.lastname: Thomas
authors.forename: Jinseon
authors.initials: J
authors.lastname: Lee
authors.forename: William G
authors.initials: WG
authors.lastname: Richards
authors.forename: David J
authors.initials: DJ
authors.lastname: Sugarbaker
authors.forename: Christopher
authors.initials: C
authors.lastname: Ducko
authors.forename: Neal
authors.initials: N
authors.lastname: Lindeman
authors.forename: J Paul
authors.initials: JP
authors.lastname: Marcoux
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.forename: Charles
authors.initials: C
authors.lastname: Lee
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000737:chemistry* / Q000235:genetics / Q000502:physiology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D015514:Oncogene Proteins, Fusion; D018719:Erb-b2 Receptor Tyrosine Kinases; C522504:EML4-ALK fusion protein, human