Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia

Mutations in the kinase domain (KD) of BCR-ABL are the most prevalent mechanism of acquired imatinib resistance in patients with chronic myeloid leukemia (CML). Here we examine predisposing factors underlying acquisition of KD mutations, evidence for acquisition of mutations before and during therap...

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Bibliographic Details
Published in:Blood 2007-10, Vol.110 (7), p.2242-2249
Main Authors: O'Hare, Thomas, Eide, Christopher A., Deininger, Michael W.N.
Format: Article
Language:English
Subjects:
Animals
Benzamides
Biological and medical sciences
Cell Proliferation
Chromosome aberrations
Drug Resistance, Neoplasm - drug effects
Drug Resistance, Neoplasm - genetics
Fusion Proteins, bcr-abl - antagonists & inhibitors
Fusion Proteins, bcr-abl - genetics
Fusion Proteins, bcr-abl - metabolism
Hematologic and hematopoietic diseases
Humans
Imatinib Mesylate
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - enzymology
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology
Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis
Medical genetics
Medical sciences
Models, Molecular
Mutation - genetics
Piperazines - chemistry
Piperazines - therapeutic use
Point Mutation - genetics
Protein Kinase Inhibitors - therapeutic use
Protein Structure, Tertiary
Pyrimidines - chemistry
Pyrimidines - therapeutic use
Recurrence
Risk Factors
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Description
Summary:Mutations in the kinase domain (KD) of BCR-ABL are the most prevalent mechanism of acquired imatinib resistance in patients with chronic myeloid leukemia (CML). Here we examine predisposing factors underlying acquisition of KD mutations, evidence for acquisition of mutations before and during therapy, and whether the detection of a KD mutation universally implies resistance. We also provide a perspective on how the second-line Abl inhibitors dasatinib and nilotinib are faring in the treatment of imatinib-resistant CML, especially in relation to specific KD mutations. We discuss the growing importance of the multi-inhibitor–resistant 315T>I mutant and the therapeutic potential that a 315T>I inhibitor would have. Last, we assess the potential of Abl kinase inhibitor combinations to induce stable responses even in advanced CML and interpret the emerging data in the context of CML pathogenesis.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2007-03-066936