Abstract
Targeted therapy with the Abl kinase inhibitor imatinib has markedly improved the outlook for patients with chronic myeloid leukemia (CML). Breakpoint cluster region (Bcr)-Abl signaling is reactivated at the time of resistance, predominantly due to mutations in the kinase domain of Bcr-Abl that interfere with drug binding. This discovery prompted the development of new Abl kinase inhibitors, among which nilotinib and dasatinib have gained regulatory approval. Despite excellent results in patients with imatinib-resistant or imatinib-intolerant CML treated with nilotinib or dasatinib, early indications suggest that: the cross-resistant Bcr-Abl(T315I) mutant is disproportionately represented among patients who relapse on these therapies; each Abl inhibitor exhibits vulnerabilities to certain kinase domain mutations. We review new inhibitors of Bcr-Abl, including preliminary information on inhibitors of Bcr-Abl(T315I) and discuss the potential of combined Abl kinase inhibitor therapy to preempt resistance. Improved Abl inhibitor therapies will be useful in achieving maximum disease control but a clinical T315I inhibitor remains a high priority.
Publication types
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Research Support, Non-U.S. Gov't
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Review
MeSH terms
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Administration, Oral
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Antineoplastic Agents / pharmacokinetics*
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use
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Benzamides
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Biological Availability
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Clinical Trials as Topic / statistics & numerical data
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Drug Design
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Drug Resistance, Neoplasm / drug effects*
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Drug Resistance, Neoplasm / genetics
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Drug Screening Assays, Antitumor
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Fusion Proteins, bcr-abl / antagonists & inhibitors*
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Fusion Proteins, bcr-abl / genetics
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Genes, abl
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HSP90 Heat-Shock Proteins / antagonists & inhibitors
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Harringtonines / pharmacology
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Harringtonines / therapeutic use
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Homoharringtonine
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Humans
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Imatinib Mesylate
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
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Mutation, Missense
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / genetics
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Piperazines / pharmacokinetics
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Piperazines / pharmacology
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Piperazines / therapeutic use
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Point Mutation
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Protein Conformation / drug effects
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Protein Kinase Inhibitors / pharmacokinetics*
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use
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Proto-Oncogene Proteins c-abl / antagonists & inhibitors
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology
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Pyrimidines / therapeutic use
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / enzymology
Substances
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Antineoplastic Agents
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Benzamides
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HSP90 Heat-Shock Proteins
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Harringtonines
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Neoplasm Proteins
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Piperazines
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Protein Kinase Inhibitors
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Pyrimidines
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Homoharringtonine
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Imatinib Mesylate
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Fusion Proteins, bcr-abl
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Proto-Oncogene Proteins c-abl