A non-smoker woman with lung adenocarcinoma is found to have an EGFR exon 19 deletion mutation. She is started on a first-generation EGFR TKI (gefitinib). After 12 months, she develops acquired resistance. The most common molecular mechanism of acquired resistance to first/second-generation EGFR TKIs is:

• A MET amplification causing EGFR-independent downstream signaling
• B PIK3CA mutation activating downstream PI3K-AKT pathway
• C Epithelial-mesenchymal transition (EMT) reducing EGFR expression
• D T790M secondary mutation in EGFR exon 20, restoring ATP-binding affinity ✓

Explanation

The T790M 'gatekeeper' secondary mutation in EGFR exon 20 accounts for approximately 50–60% of acquired resistance to first-generation (gefitinib, erlotinib) and second-generation (afatinib) EGFR TKIs. The T790M mutation substitutes methionine for threonine at position 790 in the ATP-binding pocket of EGFR kinase, restoring high ATP affinity and thereby outcompeting competitive TKI binding. Third-generation osimertinib (AZD9291) was specifically designed to overcome T790M resistance. MET amplification (~5%) and PIK3CA mutations are less common resistance mechanisms.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

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Written and medically reviewed by the StethoPrep medical team.