Imatinib resistance in CML after initial response most commonly develops through which mechanism, and which drug is used to overcome it?
- A T315I gatekeeper mutation in BCR-ABL1 kinase domain preventing imatinib binding; overcome by ponatinib (a third-generation TKI that accommodates the bulky isoleucine at 315) ✓
- B BCR-ABL1 gene amplification with overexpression of the target protein; overcome by dasatinib which has higher binding affinity
- C Activation of the Wnt/β-catenin pathway bypassing BCR-ABL1 signalling; overcome by hedgehog pathway inhibitors
- D CML stem cell quiescence making BCR-ABL1 dispensable for survival; overcome by combination with interferon-alpha
Explanation
The T315I substitution in the BCR-ABL1 kinase domain ('gatekeeper' mutation) is the most clinically critical imatinib resistance mutation. Threonine 315 normally forms a hydrogen bond with imatinib and allows an active-site steric clash with the methyl group of isoleucine; the T315I mutation eliminates this hydrogen bond and creates steric hindrance preventing binding of first-generation (imatinib) and second-generation TKIs (dasatinib, nilotinib, bosutinib). Ponatinib is the only approved TKI designed to accommodate T315I through its acetylenic linker. Asciminib (STAMP inhibitor targeting the myristoyl pocket) is a newer alternative for T315I. BCR-ABL1 amplification is a secondary resistance mechanism but responds to dose escalation or switch.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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