Recent studies move closer to answering questions about sequential therapy for anaplastic lymphoma kinase-rearranged non-small cell lung cancer

Anaplastic lymphoma kinase (ALK) fusion gene resulting from gene rearrangement was first identified in anaplastic large-cell lymphoma (ALCL) and is characterized by the fusion of nucleophosmin (NPM) and ALK genes (1). Subsequently, this type of fusion gene was described for the first time in lung cancer by Soda et al. through cDNA expression screening of surgically resected specimens from lung adenocarcinoma patients (2). Unlike the fusion gene in ALCL, this gene results from a fusion between echinoderm microtubule-associated protein-like 4 (EML4) and ALK. The two genes are positioned in opposite directions on the short arm of chromosome 2, and the inversion of this region orients the genes in the same direction leading to the formation of the EML4-ALK fusion cancer gene (2). Although ALK, a receptor tyrosine kinase, dimerizes and becomes activated by ligand binding, the gene rearrangement has been shown to cause ALK binding to the coiled-coil domain leading to its constitutive dimerization and activation without ligand binding (3). A subsequent study showed that genetically modified mice with lung-specific expression of EML4-ALK develop lung adenocarcinoma demonstrating that EML4-ALK fusion gene is a potent cancer driver gene, and since then it has been the subject of global attention in the field of oncology (4). About 3–7% of non-small cell lung cancer is thought to be positive for this fusion gene, and many of the patients are young non-smokers with adenocarcinoma and with wild-type EGFR and KRAS genes (5-8). To date several drugs that target this fusion gene have been developed (9). Currently, one first generation and two second generation ALK inhibitors are available