A molecular pathology report on a lung adenocarcinoma describes an exon 19 deletion in EGFR. The treating oncologist initiates first-line osimertinib. After 14 months, the patient progresses and repeat biopsy reveals a C797S mutation in EGFR exon 20 in trans with T790M. What is the mechanism of this acquired resistance?

• A C797S prevents covalent bond formation between osimertinib and EGFR Cys797 ✓
• B Steric clash preventing ATP-competitive binding at the gatekeeper residue
• C Amplification of downstream PIK3CA bypassing EGFR signaling
• D MET amplification conferring parallel survival signaling

Explanation

Osimertinib is a third-generation, irreversible EGFR inhibitor that forms a covalent bond with Cys797 in the EGFR kinase domain. The C797S substitution replaces cysteine with serine, abolishing the covalent attachment site and rendering osimertinib ineffective. When C797S occurs in trans (on the opposite allele from T790M), the allele bearing only C797S is accessible to first/second-generation TKIs, suggesting combination strategies. MET amplification and PIK3CA mutations are other resistance mechanisms but do not explain the structural C797S issue.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.