A 55-year-old man with CML on imatinib therapy develops resistance. Bone marrow biopsy shows BCR-ABL kinase domain mutation T315I ('gatekeeper mutation'). Why does T315I confer resistance to both first and second generation TKIs but responds to ponatinib?
- A T315I upregulates MDR1 drug efflux pump expression in leukemia cells
- B T315I activates alternative Src kinase pathway bypassing BCR-ABL
- C T315I causes conformational change preventing imatinib from binding the DFG-out inactive conformation ✓
- D T315I causes BCR-ABL protein overexpression through gene amplification
Explanation
Threonine 315 is the gatekeeper residue in BCR-ABL kinase; imatinib and most second-generation TKIs (dasatinib, nilotinib) depend on a hydrogen bond with Thr315 and require the inactive DFG-out kinase conformation. T315I substitution eliminates this critical hydroxyl group hydrogen bond contact AND creates steric clash with imatinib due to the bulkier isoleucine side chain, abrogating binding of first and second-generation inhibitors. Ponatinib (third-generation) has a carbon-carbon triple bond that bypasses the steric clash with T315I and does not require hydrogen bonding at position 315.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.