EML4-ALK
Summary
EML4-ALK is a fusion oncogene formed by inversion on chromosome 2 that drives a subset of non-small cell lung adenocarcinomas, particularly in younger nonsmokers. It is targetable by ALK tyrosine kinase inhibitors (crizotinib, alectinib).
Detail
The fusion joins EML4 (echinoderm microtubule-associated protein-like 4) to ALK (anaplastic lymphoma kinase), producing a constitutively active tyrosine kinase that drives proliferation via RAS/MAPK, PI3K/AKT, and JAK/STAT pathways. Found in ~5% of lung adenocarcinomas, more often in younger, nonsmoking patients, and is mutually exclusive with EGFR and KRAS mutations. Detected by FISH, IHC, or NGS. First-line therapy is an ALK inhibitor (alectinib preferred over crizotinib for CNS penetration). ALK rearrangements also occur in anaplastic large cell lymphoma (NPM-ALK, t(2;5)) and inflammatory myofibroblastic tumor. Resistance via secondary ALK mutations is overcome by next-generation inhibitors (lorlatinib).
Sources
- First Aid for USMLE Step 1 2024
- Robbins Basic Pathology 10th ed
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