Imatinib (Gleevec) revolutionized CML treatment. Resistance to imatinib most commonly arises through which mechanism, and what is the preferred next-line agent?

• A BCR-ABL gene amplification producing excess target; switch to higher-dose imatinib
• B Activation of alternative kinase pathways (Ras/MAPK); switch to MEK inhibitors
• C Imatinib is converted to inactive metabolite by CYP2D6 in resistant patients; poor metabolizers develop resistance
• D BCR-ABL kinase domain point mutations (most commonly T315I 'gatekeeper' mutation) preventing imatinib binding; switch to ponatinib (third-generation TKI) which is active against T315I ✓

Explanation

Imatinib resistance is predominantly mediated by point mutations in the BCR-ABL kinase domain, particularly the T315I mutation (threonine → isoleucine at position 315 — the 'gatekeeper' residue). This mutation removes a critical hydrogen bond contact with imatinib and introduces steric bulk, reducing binding affinity >1000-fold. T315I confers resistance to all first- (imatinib) and second-generation (dasatinib, nilotinib) TKIs. Ponatinib, a third-generation TKI with a carbon-carbon triple bond allowing it to bypass the T315I bulge, and asciminib (ABL1 myristoyl pocket inhibitor) are active against T315I.

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

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Written and medically reviewed by the StethoPrep medical team.