EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer

Clin Cancer Res. 2008 Jul 1;14(13):4275-83. doi: 10.1158/1078-0432.CCR-08-0168.


Purpose: 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.

Experimental design: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antineoplastic Agents / pharmacology*
  • Apoptosis
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / enzymology*
  • Cell Line, Tumor
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Gene Expression Regulation, Enzymologic*
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / enzymology*
  • Male
  • Middle Aged
  • Oncogene Proteins, Fusion / chemistry*
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / physiology
  • Receptor, ErbB-2 / metabolism


  • Antineoplastic Agents
  • EML4-ALK fusion protein, human
  • Enzyme Inhibitors
  • Oncogene Proteins, Fusion
  • Receptor, ErbB-2