Resistance to anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) in patients with lung cancer: Single mutations, compound mutations, and other mechanisms of drug resistance

Abstract Lung cancer is a leading cause of the deaths due to cancer, and the development of effective treatments has been an urgent issue. Over the last 15 years, EGFR activating mutations and fusion genes such as ALK or ROS1 have been discovered, and a number of molecular targeting drugs have been developed, that results in a remarkable antitumor effect and great extension of the survival period for the advanced lung cancer patients. In ALK rearranged cancer, many ALK tyrosine kinase inhibitors (ALK-TKIs) have been developed and 5 ALK-TKIs were approved and used in clinical setting. However, the major problem is the tumor recurrence due to the acquired resistances, and that make it difficult to achieve complete cure. The mechanism of acquired resistance varies not only from case to case, but also multiple resistance mechanisms exist in each patient with high diversity. This chapter focuses on the drug resistance mechanisms to ALK-TKIs in ALK-rearranged lung cancer, and the potential therapeutic strategies to overcome resistance.