Imatinib (Gleevec) revolutionized treatment of CML. Its mechanism of resistance through ABL kinase domain mutation at Thr315 (T315I, the 'gatekeeper' mutation) is significant because:

• A T315I mutation activates BCR-ABL constitutively, requiring higher imatinib doses
• B Threonine-315 forms a critical hydrogen bond with imatinib; isoleucine substitution removes this hydrogen bond and adds steric bulk, preventing imatinib (and most second-generation TKIs like dasatinib and nilotinib) from binding the ATP site ✓
• C The mutation causes overexpression of BCR-ABL protein overwhelming imatinib's inhibitory capacity
• D T315I induces efflux pump (ABCG2) overexpression that transports imatinib out of the cell

Explanation

Threonine-315 is the 'gatekeeper' residue of ABL kinase. Imatinib binds the inactive conformation of ABL and forms a critical hydrogen bond with the hydroxyl group of Thr315. The T315I substitution eliminates this hydrogen bond and introduces a bulkier isoleucine side chain that creates a steric clash with imatinib (and dasatinib/nilotinib which similarly require the Thr315 contact). Ponatinib (third-generation TKI) and asciminib (STAMP inhibitor binding the myristoyl pocket) were specifically developed to overcome T315I resistance.

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

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Written and medically reviewed by the StethoPrep medical team.