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EML4-ALK Fusion Gene and Efficacy of an ALK Kinase Inhibitor in Lung Cancer

Authors' Affiliations: ¹ Lowe Center for Thoracic Oncology and Departments of ² Medical Oncology and ³ Cancer Biology, Dana-Farber Cancer Institute; Departments of ⁴ Pathology and ⁵ Medicine, Brigham and Women's Hospital and Harvard Medical School; ⁶ Massachusetts General Hospital Cancer Center; ⁷ Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School; ⁸ Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts; ⁹ The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts; ¹⁰ Department of Thoracic Surgery, Samsung Medical Center; ¹¹ Sungkyunkwan University School of Medicine, Seoul, Korea; and ¹² Max-Planck Institute, Cologne, Germany

Requests for reprints: Pasi A. Jänne, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, D820A, 44 Binney Street, Boston, MA 02115. Phone: 617-632-6036; Fax: 617-582-7683; E-mail: pjanne{at}partners.org.

Purpose: The EML4-ALK fusion gene has been detected in 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.