Anaplastic Lymphoma Kinase Alterations in Human Cancer: From Pathogenesis to Targeted Therapy

Abstract

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that plays a crucial role in the development and maintenance of the nervous system. Mutations or amplification of the ALK gene can drive tumor initiation and progression across various cancer types, making ALK an important therapeutic target in oncology. Inhibition of ALK kinase activity using small molecules such as crizotinib has demonstrated significant antitumor effects; however, secondary mutations and gene amplification often lead to drug resistance.  
This review discusses emerging therapeutic strategies designed to overcome ALK inhibitor resistance. These include targeting alternative kinases within the same signaling pathways, developing next-generation ALK inhibitors based on structural (crystallographic) insights, and exploring monoclonal antibodies against ALK. Currently, five ALK tyrosine kinase inhibitors (TKIs) have received FDA approval. Novel TKIs such as ensartinib and fourth-generation ALK inhibitors for compound ALK mutations are under clinical investigation. In addition, combination therapies involving angiogenesis inhibitors and immune checkpoint inhibitors are being explored. Despite these advances, resistance mechanisms continue to emerge as the disease progresses.