EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer.
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.
Koivunen
Jussi P
JP
Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, D820A, 44 Binney Street, Boston, MA 02115, USA.
Mermel
Craig
C
Zejnullahu
Kreshnik
K
Murphy
Carly
C
Lifshits
Eugene
E
Holmes
Alison J
AJ
Choi
Hwan Geun
HG
Kim
Jhingook
J
Chiang
Derek
D
Thomas
Roman
R
Lee
Jinseon
J
Richards
William G
WG
Sugarbaker
David J
DJ
Ducko
Christopher
C
Lindeman
Neal
N
Marcoux
J Paul
JP
Engelman
Jeffrey A
JA
Gray
Nathanael S
NS
Lee
Charles
C
Meyerson
Matthew
M
Jänne
Pasi A
PA
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
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D015514:Oncogene Proteins, Fusion; D018719:Erb-b2 Receptor Tyrosine Kinases; C522504:EML4-ALK fusion protein, human