期刊
CANCER CELL
卷 26, 期 3, 页码 428-442出版社
CELL PRESS
DOI: 10.1016/j.ccr.2014.07.006
关键词
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资金
- Novartis
- Bristol-Myers Squibb (BMS)
- BMS
- Celgene
- Gilead
- ARIAD
- Georgia Cancer Coalition
- NIH/NCI [R01 CA178397]
- American Society of Hematology
- Howard Hughes Medical Institute
- NIH/NCI MERIT [R37CA065823]
- NIH [R01 CA178397, HL082978-01, 5 P01 CA049639-23]
- University of Utah Department of Medicinal Chemistry
- XSEDE supercomputers [TG-CHE120086]
- Director's Discretionary Program (Epigenetics)
- Office of Science of the U.S. Department of Energy [DE-AC02-06CH11357]
- [P30 CA042014]
- Office of Advanced Cyberinfrastructure (OAC)
- Direct For Computer & Info Scie & Enginr [0910735] Funding Source: National Science Foundation
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.
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