ALKrearranged

ALK rearranged refers to structural rearrangements of the ALK gene (anaplastic lymphoma kinase), usually creating fusion genes that encode constitutively active tyrosine kinases. The ALK gene is located on chromosome 2p23, and fusion with partner genes results in ligand-independent signaling that promotes cellular proliferation and survival.

In cancer, ALK rearrangements are best characterized in non-small cell lung cancer (NSCLC), where the EML4-ALK fusion is the most common. Other partners include KIF5B, TFG, and various additional genes. ALK rearrangements also occur in a subset of hematologic cancers, such as anaplastic large cell lymphoma with NPM1-ALK, and in inflammatory myofibroblastic tumors with various ALK fusions. ALK rearrangements are typically mutually exclusive with other oncogenic drivers.

Detection and testing rely on molecular methods. Fluorescence in situ hybridization (FISH) break-apart assays detect rearrangements, while immunohistochemistry (IHC) assesses ALK protein expression as a screening step. Confirmatory testing with RNA sequencing or targeted DNA-based next-generation sequencing (NGS) can identify fusion partners and breakpoints. Appropriate testing is recommended for certain NSCLC patients, particularly younger individuals, never-smokers, or those with adenocarcinoma histology.

Therapeutically, ALK rearrangements are targeted with ALK inhibitors. Crizotinib was the first approved therapy, followed by second- and third-generation inhibitors such as alectinib, ceritinib, brigatinib, and lorlatinib, which offer improved efficacy and central nervous system penetration. Responses are typically rapid and durable, but resistance commonly develops through secondary ALK mutations or bypass signaling pathways. Brain metastases are a notable concern in ALK-rearranged NSCLC, underscoring the importance of CNS-active inhibitors.