Imatinib resistance in chronic myeloid leukemia (CML) most commonly occurs via which mechanism, and which second-generation TKI overcomes most but NOT the T315I ('gatekeeper') mutation?

• A BCR-ABL gene amplification; overcome by dasatinib
• B Efflux pump upregulation via MDR1 overexpression; overcome by nilotinib
• C Activation of alternative Ras/MAPK pathway; overcome by bosutinib
• D Point mutations in the BCR-ABL kinase domain (especially T315I); dasatinib and nilotinib overcome most but not T315I ✓

Explanation

The most common mechanism of imatinib resistance in CML is point mutations in the BCR-ABL kinase domain that prevent imatinib from binding. Over 100 different mutations have been identified, with T315I (threonine to isoleucine at position 315, the 'gatekeeper' residue) being the most problematic — it creates steric clashes that preclude binding of imatinib, dasatinib, nilotinib, and bosutinib. Only ponatinib (third-generation TKI) and asciminib (STAMP inhibitor targeting the myristoyl pocket) are effective against T315I mutants. Dasatinib and nilotinib overcome most other kinase domain mutations.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.