Imatinib (Gleevec) was the first targeted kinase inhibitor approved for CML. Primary resistance to imatinib most commonly occurs due to:
- A BCR-ABL gene amplification, increasing the total amount of BCR-ABL kinase that overwhelms imatinib inhibition
- B Point mutations in the kinase domain of BCR-ABL (most commonly T315I 'gatekeeper mutation') that prevent imatinib binding without abolishing kinase activity ✓
- C Overexpression of MDR1 P-glycoprotein efflux pump that exports imatinib from CML blast cells
- D Upregulation of alternative SRC-family kinase pathways that bypass BCR-ABL signalling
Explanation
The most clinically significant resistance to imatinib in CML arises from point mutations in the BCR-ABL kinase domain. The T315I mutation (threonine to isoleucine at position 315 — the 'gatekeeper' residue) abolishes a critical hydrogen bond between imatinib and the kinase, sterically preventing binding while maintaining kinase activity. T315I is resistant to all first- and second-generation TKIs (dasatinib, nilotinib, bosutinib) and was historically a terminal development until ponatinib (a third-generation TKI designed computationally to accommodate the T315I bulge) and more recently asciminib (STAMP inhibitor acting at the myristoyl pocket rather than ATP site) were developed.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.