Molecular profiling of a pulmonary adenocarcinoma shows EGFR exon 19 deletion (del19). After initial response to osimertinib (third-generation EGFR TKI), the patient develops progression. The most common resistance mechanism to osimertinib as a first-line agent is:

• A Acquired T790M mutation in EGFR exon 20 that creates steric hindrance for osimertinib
• B MET amplification bypassing EGFR-driven survival signaling via KRAS-independent phosphorylation of PI3K
• C EGFR C797S point mutation in exon 20 that abolishes osimertinib covalent binding to the EGFR kinase domain ✓
• D HER2 exon 20 insertion creating a new driver mutation independent of EGFR signaling

Explanation

Osimertinib covalently binds to Cys797 in the EGFR kinase domain (exon 20), which is responsible for its irreversible inhibition of both sensitizing mutations and T790M. Acquired resistance to first-line osimertinib most commonly involves the C797S mutation in EGFR exon 20, which substitutes cysteine with serine, abolishing the covalent binding site for osimertinib and all current irreversible third-generation TKIs. T790M mutation is the mechanism of resistance to first- and second-generation EGFR TKIs (erlotinib, afatinib), and was the target for which osimertinib was originally developed; T790M in patients already on osimertinib does not confer additional resistance (osimertinib covers T790M). MET amplification and other bypass mechanisms (KRAS, BRAF, HER2) also occur but C797S is the most common on-target resistance mechanism to first-line osimertinib.

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

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Written and medically reviewed by the StethoPrep medical team.