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BCR-ABL1 Compound Mutations Combining Key Kinase Domain Positions Confer Clinical Resistance to Ponatinib in Ph Chromosome-Positive Leukemia
University of Utah, USA.
Oregon Health & Science University, USA ; Howard Hughes Medical Institute, USA.
University of Utah, USA.
University of Utah, USA.
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2014 (English)In: Cancer Cell, ISSN 1535-6108, E-ISSN 1878-3686, Vol. 26, no 3, 428-442 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2014. Vol. 26, no 3, 428-442 p.
National Category
Cancer and Oncology
Research subject
Natural Science, Biomedical Sciences
Identifiers
URN: urn:nbn:se:lnu:diva-37924DOI: 10.1016/j.ccr.2014.07.006ISI: 000341873800014OAI: oai:DiVA.org:lnu-37924DiVA: diva2:759685
Available from: 2014-10-30 Created: 2014-10-30 Last updated: 2017-02-16Bibliographically approved

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Publisher's full texthttp://www.sciencedirect.com/science/article/pii/S1535610814002980

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