Imatinib resistance in CML due to the T315I mutation (gatekeeper mutation) in BCR-ABL is overcome by which third-generation tyrosine kinase inhibitor?
- A Dasatinib
- B Bosutinib
- C Nilotinib
- D Ponatinib (AP24534) ✓
Explanation
The T315I (threonine-to-isoleucine at position 315) gatekeeper mutation in the BCR-ABL kinase domain eliminates a critical hydrogen-bonding contact with imatinib, dasatinib, nilotinib, and bosutinib, conferring resistance to all first- and second-generation ABL TKIs. Ponatinib is a third-generation TKI designed with an ethynyl linker that allows it to bind T315I-mutant BCR-ABL without the need for this threonine contact. Asciminib (STAMP inhibitor, allosteric inhibitor of ABL myristoyl pocket) also has T315I activity as a separate mechanism. Dasatinib, nilotinib, and bosutinib cannot overcome T315I resistance.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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