TY - JOUR
T1 - BCR-ABL1 Compound Mutations Combining Key Kinase Domain Positions Confer Clinical Resistance to Ponatinib in Ph Chromosome-Positive Leukemia
AU - Zabriskie, Matthew S.
AU - Eide, Christopher A.
AU - Tantravahi, Srinivas K.
AU - Vellore, Nadeem A.
AU - Estrada, Johanna
AU - Nicolini, Franck E.
AU - Khoury, Hanna J.
AU - Larson, Richard A.
AU - Konopleva, Marina
AU - Cortes, Jorge E.
AU - Kantarjian, Hagop
AU - Jabbour, Elias J.
AU - Kornblau, Steven M.
AU - Lipton, Jeffrey H.
AU - Rea, Delphine
AU - Stenke, Leif
AU - Barbany, Gisela
AU - Lange, Thoralf
AU - Hernández-Boluda, Juan Carlos
AU - Ossenkoppele, Gert J.
AU - Press, Richard D.
AU - Chuah, Charles
AU - Goldberg, Stuart L.
AU - Wetzler, Meir
AU - Mahon, Francois Xavier
AU - Etienne, Gabriel
AU - Baccarani, Michele
AU - Soverini, Simona
AU - Rosti, Gianantonio
AU - Rousselot, Philippe
AU - Friedman, Ran
AU - Deininger, Marie
AU - Reynolds, Kimberly R.
AU - Heaton, William L.
AU - Eiring, Anna M.
AU - Pomicter, Anthony D.
AU - Khorashad, Jamshid S.
AU - Kelley, Todd W.
AU - Baron, Riccardo
AU - Druker, Brian J.
AU - Deininger, Michael W.
AU - O'Hare, Thomas
N1 - Publisher Copyright:
© 2014 Elsevier Inc.
PY - 2014
Y1 - 2014
N2 - 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-ABL1T315I 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. Invitro 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.
AB - 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-ABL1T315I 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. Invitro 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.
UR - http://www.scopus.com/inward/record.url?scp=84908364892&partnerID=8YFLogxK
U2 - 10.1016/j.ccr.2014.07.006
DO - 10.1016/j.ccr.2014.07.006
M3 - Article
C2 - 25132497
AN - SCOPUS:84908364892
SN - 1535-6108
VL - 26
SP - 428
EP - 442
JO - Cancer Cell
JF - Cancer Cell
IS - 3
ER -