A patient with CML on imatinib develops resistance. BCR-ABL kinase domain sequencing reveals a T315I 'gatekeeper' mutation. Which second-generation TKI retains activity against T315I?
- A Nilotinib
- B Dasatinib
- C Ponatinib ✓
- D Bosutinib
Correct answer: C. Ponatinib
Explanation
The T315I gatekeeper mutation in BCR-ABL eliminates a critical hydrogen bond and creates steric interference that renders all second-generation TKIs (nilotinib, dasatinib, bosutinib) ineffective. Ponatinib is a third-generation TKI specifically engineered with a carbon-carbon triple bond that accommodates the T315I substitution, retaining inhibitory activity. Asciminib (STAMP inhibitor) also has activity against T315I at higher doses. This mutation is present in 15–20% of imatinib-resistant CML patients.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.