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Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer

Abstract

Improvement in the clinical outcome of lung cancer is likely to be achieved by identification of the molecular events that underlie its pathogenesis. Here we show that a small inversion within chromosome 2p results in the formation of a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene in non-small-cell lung cancer (NSCLC) cells. Mouse 3T3 fibroblasts forced to express this human fusion tyrosine kinase generated transformed foci in culture and subcutaneous tumours in nude mice. The EML4–ALK fusion transcript was detected in 6.7% (5 out of 75) of NSCLC patients examined; these individuals were distinct from those harbouring mutations in the epidermal growth factor receptor gene. Our data demonstrate that a subset of NSCLC patients may express a transforming fusion kinase that is a promising candidate for a therapeutic target as well as for a diagnostic molecular marker in NSCLC.

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Figure 1: Gene fusion between EML4 and ALK.
Figure 2: Transforming activity of EML4–ALK variant 1.
Figure 3: Screening of NSCLC specimens for EML4–ALK variant 1 mRNA.
Figure 4: Inhibition of the growth of BA/F3 cells expressing EML4–ALK variant 1 by a chemical inhibitor of ALK.

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Acknowledgements

We thank R. Moriuchi for suggestions.

Author Contributions M.S. and Y.L.C. contributed equally to this work. M.S., S.-i.F., H.W. and H.H. constructed the cDNA library and screened for transforming genes. Y.L.C. sequenced the EML4–ALK cDNA and conducted the experiments with BA/F3 cells. Y.Y. and S.T. searched for EGFR and KRAS mutations. M.E., S.I., K.K., M.B., S.O., S.T., Y.I. and H.A. performed RT–PCR for EML4–ALK transcripts in cancer specimens. T.N., Y. Sohara, Y. Sugiyama and H.M. designed the overall project, and H.M. wrote the manuscript. All authors discussed the results and commented on the manuscript.

The nucleotide sequences of EML4–ALK variant 1 and variant 2 cDNA have been deposited in DDBJ, EMBL and GenBank under the accession numbers AB274722 and AB275889, respectively.

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Correspondence to Hiroyuki Mano.

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Soda, M., Choi, Y., Enomoto, M. et al. Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer. Nature 448, 561–566 (2007). https://doi.org/10.1038/nature05945

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