We discovered the EML4-ALK fusion gene in 2007. Through a small inversion within the short arm of chromosome 2, a 5'-part of EML4 becomes fused mainly to intron 19 of ALK, resulting in a production of a constitutively active and highly oncogenic tyrosine kinase. EML4-ALK is highly enriched in lung adenocarcinoma in young onset and in never- or light-smokers. Transgenic mice expressing EML4-ALK generates hundreds of lung adenocarcinoma nodules soon after birth, but such nodules are rapidly cleared in response to a treatment with ALK inhibitors, suggesting that EML4-ALK-positive tumors are profoundly addicted to its elevated enzymatic activity.
In response to such observation, a large number of ALK inhibitors are currently under development or clinical trials, and, a marked efficacy of the first inhibitor (crizotinib) was already reported with a disease control rate of ∼90%. As of 26 August 2011, crizotinib was approved as a therapeutic drug by US FDA, which was the record-breaking speed in the history of cancer drug development.
Unfortunately, tumors treated with ALK inhibitors frequently become refractory to the compounds, and, from such specimens, a number of amino acid substitutions (including that at the gate-keeper position) within EML4-ALK were shown responsible for the acquired drug resistance. The molecular mechanisms underlining the resistance among EML4-ALK-wild tumors, however, remain elusive.
The discovery of EML4-ALK and a remarkable success of ALK inhibitors have triggered a screening ofEML4-ALK in other tumors as well as of other ALK fusions, leading to the identification of KIF5B-ALK in lung cancer and VCL-ALK in renal medullary carcinoma. The story of EML4-ALK has revealed that (i) ALK contributes to a wide range of human cancers (ALKoma) through a variety of activation mechanism, and (ii) fusion-type tyrosine kinases are novel and suitable therapeutic targets in epithelial tumors.