Foundations · Year 1 · from Foundations
Case 2: EGFR-Mutant Lung Cancer (Receptor Tyrosine Kinase Signaling)
Clinical Image
Source: Wikipedia - Epidermal growth factor receptor - CC BY-SA 3.0
Case Presentation
A 58-year-old never-smoking woman presents with cough and dyspnea. Chest CT reveals a large right lower lobe mass with mediastinal lymphadenopathy. CT-guided biopsy confirms lung adenocarcinoma. Molecular testing is performed and reveals an EGFR exon 19 deletion mutation. The oncologist explains that EGFR is a receptor tyrosine kinase (RTK) that normally requires ligand binding for activation. However, certain mutations cause constitutive, ligand-independent activation, driving uncontrolled proliferation through the RAS-MAPK and PI3K-AKT pathways. EGFR mutations are more common in never-smokers, women, and patients of Asian descent. She is started on osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI) that binds the ATP-binding pocket of EGFR and blocks its kinase activity. Her tumor shows dramatic response, with significant shrinkage on follow-up imaging. After 18 months, her disease progresses. Repeat biopsy reveals an EGFR C797S resistance mutation that prevents osimertinib binding. She is transitioned to combination therapy targeting the resistance mechanism. This case illustrates both the success of targeted therapy and the challenge of acquired resistance.
Key Learning Points
- EGFR is a receptor tyrosine kinase; ligand binding induces dimerization and trans-autophosphorylation, creating docking sites for adaptor proteins that activate RAS-MAPK and PI3K-AKT pathways
- Activating EGFR mutations cause constitutive signaling independent of ligand; EGFR TKIs (gefitinib, erlotinib, osimertinib) block kinase activity by competing for the ATP binding site
- Acquired resistance commonly develops through secondary mutations, pathway bypass, or phenotypic transformation, highlighting the need for repeat molecular testing at progression