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 - Funding Information:
The authors acknowledge the mentorship of Professor John M. Goldman (1938-2013), Imperial College London, and dedicate this paper to his legacy. We thank ARIAD Pharmaceuticals for nonfinancial support and permission to perform an investigator-initiated companion study (P.I.: M.D.) to study mechanisms of resistance to ponatinib in patients treated on the PACE trial. We thank Qian Yu, David J. Anderson, and Ira L. Kraft for technical assistance. H.J.K. thanks the Georgia Cancer Coalition for a tissue bank-supporting grant. We acknowledge support in conjunction with grant P30 CA042014 awarded to the Huntsman Cancer Institute (T.O.). T.O. is supported by the NIH / NCI ( R01 CA178397 ). S.K.T is a recipient of 2013 Research Training Award for Fellows from the American Society of Hematology . A.M.E. is currently a Fellow of the Leukemia & Lymphoma Society ( 5090-12 ). This work was supported by Howard Hughes Medical Institute and NIH / NCI MERIT award R37CA065823 (B.J.D.). M.W.D. is supported by the NIH ( HL082978-01 , 5 P01 CA049639-23 and R01 CA178397 ), was a Leukemia & Lymphoma Society (LLS) Scholar in Clinical Research ( 7036-01 ), and is an investigator on LLS SCOR7005-11. R.B. acknowledges funding from the University of Utah Department of Medicinal Chemistry, a computing allocation at the XSEDE supercomputers (award TG-CHE120086 ), and the Director’s Discretionary Program (Epigenetics), which used resources of the Argonne Leadership Computing Facility, supported by the Office of Science of the U.S. Department of Energy ( DE-AC02-06CH11357 ).
Funding Information:
Oregon Health & Science University (OHSU) and B.J.D. have a financial interest in MolecularMD. Technology used in this research has been licensed to MolecularMD. This potential conflict of interest has been reviewed and managed by the OHSU Conflict of Interest in Research Committee and Integrity Oversight Council. OHSU also has clinical trial contracts with Novartis and Bristol-Myers Squibb (BMS) to pay for patient costs, nurse and data manager salaries, and institutional overhead. B.J.D. does not derive salary, nor does his laboratory receive funds, from these contracts. M.W.D. served on advisory boards and as a consultant for BMS, ARIAD, and Novartis and receives research funding from BMS, Celgene, Novartis, and Gilead. H.M.K. receives research funding from ARIAD. E.J.J. receives consultancy fees from ARIAD. S.S. is a consultant for BMS, Novartis, and ARIAD.
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.
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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 -
