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.
MeSH terms
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3T3 Cells
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Amino Acid Sequence
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Anaplastic Lymphoma Kinase
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Animals
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Carcinoma, Non-Small-Cell Lung / drug therapy
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Carcinoma, Non-Small-Cell Lung / genetics*
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Carcinoma, Non-Small-Cell Lung / metabolism
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Cycle Proteins / genetics*
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Cell Cycle Proteins / metabolism
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Cell Proliferation / drug effects
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Cell Transformation, Neoplastic / genetics*
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Cell Transformation, Neoplastic / pathology
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Chromosome Inversion / genetics
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Chromosomes, Human, Pair 2 / genetics
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Humans
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Lung Neoplasms / drug therapy
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Lung Neoplasms / genetics*
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Mice
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Microtubule-Associated Proteins / genetics*
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Microtubule-Associated Proteins / metabolism
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Molecular Sequence Data
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Mutation / genetics
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Oncogene Proteins, Fusion / antagonists & inhibitors
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Oncogene Proteins, Fusion / chemistry
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Oncogene Proteins, Fusion / genetics*
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Oncogene Proteins, Fusion / metabolism*
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / genetics*
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Protein-Tyrosine Kinases / metabolism
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Receptor Protein-Tyrosine Kinases
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Serine Endopeptidases / genetics*
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Serine Endopeptidases / metabolism
Substances
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Cell Cycle Proteins
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EML4-ALK fusion protein, human
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Microtubule-Associated Proteins
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Oncogene Proteins, Fusion
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ALK protein, human
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Alk protein, mouse
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Anaplastic Lymphoma Kinase
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Protein-Tyrosine Kinases
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Receptor Protein-Tyrosine Kinases
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EML4 protein, human
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Serine Endopeptidases
Associated data
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GENBANK/AB274722
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GENBANK/AB275889