Imatinib (a BCR-ABL tyrosine kinase inhibitor) resistance in CML commonly develops due to which mutation?

• A T315I (threonine to isoleucine) mutation in the BCR-ABL kinase domain gatekeeper residue ✓
• B Amplification of the MYC oncogene bypassing BCR-ABL signalling
• C Upregulation of multidrug resistance protein 2 (MRP2)-mediated efflux
• D Loss of BCR-ABL expression via promoter methylation

Explanation

The T315I 'gatekeeper' mutation (threonine-315 to isoleucine) is the most important and clinically prevalent mechanism of imatinib (and second-generation TKI: dasatinib/nilotinib) resistance. The threonine-315 hydroxyl group forms a critical hydrogen bond with imatinib; substitution with the bulkier isoleucine sterically prevents drug binding and also creates a hydrophobic favourable environment for ATP. Only ponatinib (third-generation TKI) and asciminib (allosteric inhibitor) are active against T315I.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.