Imatinib (Gleevec) revolutionised CML treatment. It acts as a competitive inhibitor of the ATP-binding site of BCR-ABL tyrosine kinase. Resistance to imatinib most commonly develops through:

• A Amplification of MDR1 gene (P-glycoprotein overexpression)
• B Point mutations in the BCR-ABL kinase domain, particularly T315I ('gatekeeper' mutation) ✓
• C Upregulation of STAT3 signalling bypassing BCR-ABL
• D Deletion of chromosome 9 removing the BCR-ABL fusion gene

Explanation

Imatinib resistance in CML is most commonly caused by point mutations in the BCR-ABL kinase domain that prevent drug binding while preserving kinase activity. The T315I ('gatekeeper') mutation at the threonine-315 residue eliminates a critical hydrogen bond contact and sterically blocks imatinib as well as second-generation TKIs (dasatinib, nilotinib); only third-generation ponatinib is active against T315I-mutant BCR-ABL. MDR1 overexpression can contribute but is a less frequent mechanism.

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

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Written and medically reviewed by the StethoPrep medical team.