Imatinib revolutionised the treatment of CML. Resistance to imatinib most commonly arises from which mechanism, and which second-generation TKI overcomes this?

• A BCR-ABL gene amplification increasing kinase copy number; overcome by dasatinib which binds more copies simultaneously
• B Point mutations in the BCR-ABL kinase domain (particularly T315I gate-keeper mutation and others) preventing imatinib binding; T315I is overcome by ponatinib (a third-generation TKI) ✓
• C Upregulation of P-glycoprotein efflux pump exporting imatinib; overcome by dasatinib which is not a P-gp substrate
• D Activation of alternative survival pathway (PI3K/Akt) bypassing BCR-ABL; overcome by adding everolimus to imatinib

Explanation

The most common mechanism of acquired imatinib resistance in CML is point mutations in the BCR-ABL kinase domain that prevent imatinib from binding to its binding pocket. Over 100 mutations have been described. Second-generation TKIs dasatinib and nilotinib overcome most imatinib-resistant mutations by binding BCR-ABL in an open conformation. However, the T315I 'gatekeeper' mutation (threonine to isoleucine at position 315) confers resistance to imatinib, dasatinib, nilotinib, and bosutinib because it eliminates a critical hydrogen bond and introduces steric hindrance. Ponatinib (a third-generation TKI) is specifically designed to accommodate the T315I mutation and is used in T315I-positive cases.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.