A patient with CML is started on imatinib. After 2 years, he develops resistance. The MOST common mechanism is:

• A Point mutations in the BCR-ABL kinase domain (particularly T315I 'gatekeeper' mutation) preventing imatinib binding ✓
• B Amplification of MDR1 gene increasing P-glycoprotein efflux of imatinib
• C Metabolism of imatinib to inactive metabolites by upregulated CYP3A4
• D Epigenetic silencing of the BCR-ABL gene by DNA methylation

Explanation

Imatinib resistance in CML most commonly arises from point mutations in the BCR-ABL kinase domain that impair drug binding. Over 100 resistance mutations have been described; the T315I (threonine to isoleucine at position 315) 'gatekeeper' mutation is the most clinically significant because it abolishes a critical hydrogen bond with imatinib and confers resistance to second-generation TKIs (dasatinib, nilotinib) as well. Ponatinib is the only approved TKI active against T315I BCR-ABL. BCR-ABL amplification (not silencing) also contributes to resistance but is less common than 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.