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