A 55-year-old never-smoker woman has a lung adenocarcinoma with EGFR exon 19 deletion. She receives osimertinib (third-generation EGFR TKI). After 14 months, she progresses with a new EGFR C797S mutation. The C797S mutation causes resistance by:

• A Activating the MAPK bypass pathway through KRAS mutation
• B Amplifying MET to bypass EGFR signaling dependence
• C Upregulating ABCB1 drug efflux transporter
• D Preventing drug binding by altering the ATP binding pocket cysteine required for covalent bond formation ✓

Explanation

Osimertinib is a third-generation EGFR TKI that covalently binds to cysteine 797 (C797) in the ATP-binding pocket of EGFR, overcoming the T790M resistance mutation that blocked earlier TKIs. The C797S mutation substitutes serine for cysteine at position 797, eliminating the nucleophilic cysteine required for osimertinib's irreversible covalent bond. This renders osimertinib unable to bind EGFR effectively, causing resistance. The C797S mutation is found in ~10–26% of osimertinib-resistant tumors. Its therapeutic implication depends on whether it is in cis or trans with T790M: cis combination is resistant to all current EGFR TKIs; trans may be sensitive to first + third generation combination.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.