ALK

ALK, short for anaplastic lymphoma kinase, is a receptor tyrosine kinase of the insulin receptor superfamily. It is primarily expressed in the developing nervous system, with limited expression in some adult tissues. The receptor features an extracellular ligand-binding domain, a single transmembrane segment, and an intracellular tyrosine kinase domain. Endogenous ligands include midkine and pleiotrophin, and ligand engagement activates signaling pathways such as RAS-ERK, PI3K-AKT, and JAK-STAT that regulate cell growth and survival.

In cancer, ALK can be dysregulated by gene rearrangements that generate constitutively active fusion proteins. The best-known examples are NPM1-ALK in anaplastic large cell lymphoma and EML4-ALK in a subset of non-small cell lung cancer. Additional ALK fusions have been identified in inflammatory myofibroblastic tumors, neuroblastoma, and other malignancies. These alterations drive oncogenic signaling and can be targeted therapeutically.

Detection of ALK alterations relies on multiple methods, including fluorescence in situ hybridization (FISH) to identify gene rearrangements, immunohistochemistry (IHC) to detect ALK protein overexpression, and RT-PCR to identify specific fusion transcripts.

Therapy for ALK-rearranged cancers has been transformed by ALK inhibitors. First-generation crizotinib is followed by second-generation inhibitors such as ceritinib, alectinib, and brigatinib, and a third-generation agent, lorlatinib, designed to overcome resistance and address central nervous system disease. Resistance mechanisms include secondary kinase mutations and bypass signaling, motivating ongoing research into combination strategies and next-generation inhibitors. ALK testing and targeted therapy have become standard care in many ALK-positive cancers, improving outcomes for affected patients.