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rdf:type |
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lifeskim:mentions |
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pubmed:dateCreated |
2008-10-24
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pubmed:abstractText |
Imatinib was the first BCR-ABL-targeted agent approved for the treatment of patients with chronic myeloid leukemia (CML) and confers significant benefit for most patients; however, a substantial number of patients are either initially refractory or develop resistance. Point mutations within the ABL kinase domain of the BCR-ABL fusion protein are a major underlying cause of resistance. Of the known imatinib-resistant mutations, the most frequently occurring involve the ATP-binding loop (P-loop). In vitro evidence has suggested that these mutations are more oncogenic with respect to other mutations and wild type BCR-ABL. Dasatinib and nilotinib have been approved for second-line treatment of patients with CML who demonstrate resistance (or intolerance) to imatinib. Both agents have marked activity in patients resistant to imatinib; however, they have differential activity against certain mutations, including those of the P-loop. Data from clinical trials suggest that dasatinib may be more effective vs. nilotinib for treating patients harboring P-loop mutations. Other mutations that are differentially sensitive to the second-line tyrosine kinase inhibitors (TKIs) include F317L and F359I/V, which are more sensitive to nilotinib and dasatinib, respectively. P-loop status in patients with CML and the potency of TKIs against P-loop mutations are key determinants for prognosis and response to treatment. This communication reviews the clinical importance of P-loop mutations and the efficacy of the currently available TKIs against them.
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/18828913-10219069,
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:issn |
1756-8722
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:volume |
1
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
15
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pubmed:meshHeading |
pubmed-meshheading:18828913-Animals,
pubmed-meshheading:18828913-Antineoplastic Agents,
pubmed-meshheading:18828913-Drug Resistance, Neoplasm,
pubmed-meshheading:18828913-Fusion Proteins, bcr-abl,
pubmed-meshheading:18828913-Humans,
pubmed-meshheading:18828913-Leukemia, Myelogenous, Chronic, BCR-ABL Positive,
pubmed-meshheading:18828913-Mutation,
pubmed-meshheading:18828913-Piperazines,
pubmed-meshheading:18828913-Pyrimidines
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pubmed:year |
2008
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pubmed:articleTitle |
P-loop mutations and novel therapeutic approaches for imatinib failures in chronic myeloid leukemia.
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pubmed:affiliation |
Division of Hematology/Oncology, New York Medical College, Valhalla, NY 10595, USA. cangshundong@163.com
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pubmed:publicationType |
Journal Article,
Review,
Research Support, Non-U.S. Gov't
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