A 55-year-old woman with a lung adenocarcinoma undergoes molecular profiling. The tumor harbors an EML4-ALK fusion. Which mechanism best explains why this fusion protein drives malignant transformation?
- A Constitutive activation of ALK tyrosine kinase independent of ligand binding ✓
- B Overexpression of wild-type ALK leading to receptor autophosphorylation
- C Loss of the ALK extracellular ligand-binding domain causing nuclear translocation
- D Fusion creates a dominant-negative inhibitor of EGFR signaling
Correct answer: A. Constitutive activation of ALK tyrosine kinase independent of ligand binding
Explanation
The EML4-ALK gene fusion results in a chimeric protein where the N-terminal EML4 coiled-coil domain mediates constitutive dimerization, rendering ALK kinase permanently active without ligand. This drives continuous RAS-MAPK and PI3K-AKT signaling. The fusion does not involve nuclear translocation or EGFR inhibition; it is not overexpression of wild-type ALK but rather an aberrant constitutively active chimera.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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