Discovery of a lung cancer oncogene, EML4-ALK, and its clinical application

Abstract

We discovered a novel fusion-type oncogene EMU (echinoderm microtubule-associated protein-like 4)-ALK (anaplastic lymphoma kinase) in 4-5% of human lung cancers, which is generated via a small inversion within the short arm of human chromosome 2 (inv [2p]). Through this process, an N-terminal half of the EML4 protein becomes fused to the intracellular tyrosine kinase area of ALK. A coiled-coil region within EML4 leads to constitutive dimerization of EML4-ALK, and thereby induces a marked transforming activity in the fusion kinase. Transgenic mice expressing EML4-ALK in lung epithelial cells generate hundreds of lung cancer nodules soon after birth, but such nodules rapidly disappear in response to the administration of an ALK inhibitor. Therefore, EML4-ALK is likely to be the essential growth driver in those tumors in which fusion occurs. Furthermore, targeting the catalytic activity of EML4-ALK could be a promising means of treating such types of cancer. Phase I/II clinical trials with an ALK inhibitor have already been completed on patients positive for EML4-ALK, which have confirmed the marked therapeutic efficacy of the compound. Today, a phase III trial with the compound is ongoing worldwide. We hope our discovery will thus positively affect the prognosis of hundreds of thousands of lung cancer patients arround the world. © 2010 The Japan Lung Cancer Society.