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EnglishPonatinib 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.
| Titolo: | BCR-ABL1 Compound Mutations Combining Key Kinase Domain Positions Confer Clinical Resistance to Ponatinib in Ph Chromosome-Positive Leukemia |
| Autore/i: | 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, MICHELE; SOVERINI, SIMONA; ROSTI, GIANANTONIO; 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. |
| Autore/i Unibo: | |
| Anno: | 2014 |
| Rivista: | |
| Digital Object Identifier (DOI): | http://dx.doi.org/10.1016/j.ccr.2014.07.006 |
| 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. |
| Data stato definitivo: | 2015-11-17T09:45:48Z |
| Appare nelle tipologie: | 1.01 Articolo in rivista |
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