Drug resistance in anaplastic lymphoma kinase-rearranged lung cancer

The anaplastic lymphoma kinase (ALK) gene encodes a receptor tyrosine kinase, and many kinds of ALK fusion genes have been found in a variety of carcinomas. There is almost no detectable expression of ALK in adults. However, through ALK gene rearrangement, the resultant ALK fusion protein is aberrantly overexpressed and dimerized through the oligomerization domains, such as the coiled-coil domain, in the fusion partner that induces abnormal constitutive activation of ALK tyrosine kinase. This results in dysregulated cell proliferation. ALK gene rearrangement has been observed in 3%-5% of non-small-cell lung cancers, and multiple ALK inhibitors have been developed for the treatment of ALK-positive lung cancer. Among those inhibitors, in Japan, 3 (4 in the USA) ALK tyrosine kinase inhibitors (TKIs) have been approved and are currently used in clinics. All of the currently approved ALK-TKIs have been shown to induce marked tumor regression in ALK-rearranged non-small-cell lung cancer; however, tumors inevitably relapse because of acquired resistance within a few years. This review focuses on ALK-TKIs, their resistance mechanisms, and the potential therapeutic strategies to overcome resistance.