Ponatinib is the only currently approved tyrosine kinase inhibitor (TKI) that suppresses all BCR-ABL1 single mutants in Philadelphia chromosome-positive (Ph(+)) leukemia, including the recalcitrant BCR-ABL1(T315I) mutant. However, emergence of compound mutations in a BCR-ABL1 allele may confer ponatinib resistance. We found that clinically reported BCR-ABL1 compound mutants center on 12 key positions and confer varying resistance to imatinib, nilotinib, dasatinib, ponatinib, rebastinib, and bosutinib. T315I-inclusive compound mutants confer high-level resistance to TKIs, including ponatinib. In vitro resistance profiling was predictive of treatment outcomes in Ph(+) leukemia patients. Structural explanations for compound mutation-based resistance were obtained through molecular dynamics simulations. Our findings demonstrate that BCR-ABL1 compound mutants confer different levels of TKI resistance, necessitating rational treatment selection to optimize clinical outcome.

BCR-ABL1 Compound Mutations Combining Key Kinase Domain Positions Confer Clinical Resistance to Ponatinib in Ph Chromosome-Positive Leukemia

BACCARANI, MICHELE;SOVERINI, SIMONA;ROSTI, GIANANTONIO;
2014

Abstract

Ponatinib is the only currently approved tyrosine kinase inhibitor (TKI) that suppresses all BCR-ABL1 single mutants in Philadelphia chromosome-positive (Ph(+)) leukemia, including the recalcitrant BCR-ABL1(T315I) mutant. However, emergence of compound mutations in a BCR-ABL1 allele may confer ponatinib resistance. We found that clinically reported BCR-ABL1 compound mutants center on 12 key positions and confer varying resistance to imatinib, nilotinib, dasatinib, ponatinib, rebastinib, and bosutinib. T315I-inclusive compound mutants confer high-level resistance to TKIs, including ponatinib. In vitro resistance profiling was predictive of treatment outcomes in Ph(+) leukemia patients. Structural explanations for compound mutation-based resistance were obtained through molecular dynamics simulations. Our findings demonstrate that BCR-ABL1 compound mutants confer different levels of TKI resistance, necessitating rational treatment selection to optimize clinical outcome.
2014
Zabriskie, M.S.; Eide, C.A.; Tantravahi, S.K.; Vellore, N.A.; Estrada, J.; Nicolini, F.E.; Khoury, H.J.; Larson, R.A.; Konopleva, M.; Cortes, J.E.; Kantarjian, H.; Jabbour, E.J.; Kornblau, S.M.; Lipton, J.H.; Rea, D.; Stenke, L.; Barbany, G.; Lange, T.; Hernandez-Boluda, J.-C.; Ossenkoppele, G.J.; Press, R.D.; Chuah, C.; Goldberg, S.L.; Wetzler, M.; Mahon, F.-X.; Etienne, G.; Baccarani, M.; Soverini, S.; Rosti, G.; Rousselot, P.; Friedman, R.; Deininger, M.; Reynolds, K.R.; Heaton, W.L.; Eiring, A.M.; Pomicter, A.D.; Khorashad, J.S.; Kelley, T.W.; Baron, R.; Druker, B.J.; Deininger, M.W.; O'Hare, T.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/519526
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