Targeting ALK Tyrosine Kinase in Lung Cancer

ABSTRACT In order to discover novel transforming genes in cancer specimens, we developed a sensitive retroviral expression library system for full-length cDNAs. By using this technology coupled with a focus formation assay with mouse 3T3 cells, we could discover, from a specimen of non-small cell lung cancer (NSCLC), a novel oncogenic fusion-type tyrosine kinase EML4-ALK. Both of EML4 and ALK genes are mapped closely on the same short arm of human chromosome 2, but a small inversion involving these two loci, inv(2)(p21p23), leads to fuse the 5'-part of EML4 to the 3′ part of ALK encoding the tyrosine kinase domain. Transgenic mice expressing EML4-ALK in lung epithelial cells developed hundreds of adenocarcinoma nodules in both lungs only at a few weeks after birth, and oral administration of a specific inhibitor to ALK successfully cleared such nodules from the mice, proving in vivo that EML4-ALK is the primary genetic event to trigger cancer, and, therefore, specific inhibitors against EML4-ALK could be a novel and effective drug.Currently, a number of clinical trials with ALK inhibitors are ongoing worldwide, and the result of phase I/II studies with one of such compound, crizotinib, was made public, demonstrating the dramatic therapeutic efficacy of the compound against EML4-ALK-positive NSCLC. Further, crizotinib has just been approved as a therapeutic drug by US FDA in a record breaking speed of drug development. To help individuals with EML4-ALK-positive NSCLC in Japan, we started from early 2009 ‘ALK Lung Cancer Study group (ALCAS)’, a nation-wide diagnostic network for such tumors. Through the ALCAS initiative, we also noticed a patient who was once effectively treated with crizotinib, but later underwent abrupt relapse. Molecular analyses of these specimens led to the discovery of secondary mutations C1156Y and L1196M within EML4-ALK accounting for the observed drug tolerance. Our data thus demonstrate that a subset of lung cancer express previously unidentified fusion kinases that are promising candidates for a therapeutic target as well as for a diagnostic molecular marker for this intractable disorder.