Imatinib revolutionized CML treatment by targeting the BCR-ABL kinase. The mechanism by which resistance develops most commonly to imatinib is:

• A Point mutations in the BCR-ABL kinase domain (most commonly T315I gatekeeper mutation) that prevent imatinib binding ✓
• B Overexpression of P-glycoprotein (MDR1) causing increased drug efflux from cells
• C Amplification of the BCR-ABL gene producing excess target protein that overwhelms drug concentration
• D Methylation of the imatinib metabolism gene CYP3A4, increasing drug clearance

Explanation

The most common mechanism of acquired imatinib resistance in CML is point mutations in the BCR-ABL kinase domain that alter the binding pocket and prevent imatinib from occupying it. Over 100 such mutations have been identified; the T315I mutation (threonine to isoleucine at position 315) is the most important 'gatekeeper' mutation because it confers resistance not only to imatinib but also to second-generation TKIs (dasatinib, nilotinib). Ponatinib (third-generation) and asciminib (STAMP inhibitor) were developed specifically to overcome T315I resistance. BCR-ABL gene amplification and P-gp overexpression are secondary mechanisms.

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

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Written and medically reviewed by the StethoPrep medical team.