Imatinib is a BCR-ABL tyrosine kinase inhibitor for CML. Resistance develops in most patients over time. The most common mechanism of imatinib resistance in CML is:

• A Transcriptional downregulation of BCR-ABL, reducing the target for imatinib
• B Point mutations in the BCR-ABL kinase domain (most notably T315I — the 'gatekeeper' mutation) that prevent imatinib binding ✓
• C Overexpression of MDR1/P-glycoprotein causing increased efflux of imatinib from CML cells
• D Activation of the JAK2-STAT3 pathway bypassing BCR-ABL signalling

Explanation

The most common and clinically important mechanism of imatinib resistance in CML is acquisition of point mutations in the BCR-ABL kinase domain that reduce or abolish imatinib binding. Over 100 mutations have been identified, but T315I (threonine to isoleucine at position 315 — the 'gatekeeper' residue) is the most problematic as it confers resistance to imatinib AND to the 2nd-generation TKIs dasatinib and nilotinib. Only ponatinib (3rd-generation) and asciminib (STAMP inhibitor targeting ABL myristoyl pocket) are active against T315I mutation. BCR-ABL gene amplification is the second mechanism. P-gp overexpression contributes but is not the primary mechanism.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.