Abstract
Using an original cDNA expression library system, we discovered a novel fusion oncogene between EML4 and ALK that can be identified in 4-5% of non-small cell lung cancer (NSCLC) cases. Fusion to EML4 induces a constitutive dimerization of the ALK kinase domain, and thereby its marked activation. Transgenic mice expressing EML4-ALK in lung generated hundreds of adenocarcinoma nodules soon after birth, but the oral administration of an ALK inhibitor successfully resolved these nodules. Our discovery led to the swift development of ALK-inhibitors, and one such compound, crizotinib, has already demonstrated outstanding efficacy in a phase I/II clinical trial. We observed a patient who was effectively treated once with crizotinib, but relapse occurred 6 months later. Molecular analysis of histological specimens led to a discovery of secondary mutations within EML4-ALK, accounting for the observed drug tolerance. Our data thus demonstrate that a subset of lung cancer expresses previously unidentified fusion kinases that could be a therapeutic target as well as a diagnostic molecular marker for this intractable disorder.
