A 58-year-old man with a lung adenocarcinoma is found to have an EGFR exon 20 insertion mutation. Which of the following best explains why first-generation EGFR tyrosine kinase inhibitors (erlotinib/gefitinib) show limited efficacy against this mutation compared to exon 19 deletions?

• A Exon 20 insertions abolish EGFR kinase activity entirely
• B Exon 20 insertions activate alternate RAS-RAF-MEK signalling that bypasses EGFR
• C Exon 20 insertions cause EGFR nuclear translocation away from membrane targets
• D Exon 20 insertions create steric hindrance in the ATP-binding cleft, preventing drug binding ✓

Explanation

EGFR exon 20 insertions insert amino acids just after the C-helix of the kinase domain, causing its displacement into the drug-binding pocket (ATP cleft). This structural change creates steric obstruction that prevents first-generation TKIs (which bind the inactive conformation) from docking effectively, while exon 19 deletions stabilise the active conformation to which these drugs bind with high affinity. Exon 20 insertions maintain kinase activity and do not redirect signalling through alternate pathways or cause nuclear sequestration.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.