Mechanisms of resistance to STI571 in Philadelphia chromosome-associated leukemias

Philadelphia chromosome-associated leukemias are among the most well-understood human malignancies. The importance of BCR-ABL enzymatic activity in the proliferation of the leukemic clone has been confirmed by the high response rates of these leukemias to the ABL-selective tyrosine kinase inhibitor...

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Bibliographic Details
Published inOncogene Vol. 22; no. 47; pp. 7389 - 7395
Main Authors Shah, Neil P, Sawyers, Charles L
Format Journal Article
LanguageEnglish
Published England Nature Publishing Group 20.10.2003
Subjects
ABL gene
Abl protein
Amino Acid Sequence
Animals
Apoptosis
BCR gene
BCR protein
Benzamides
Bone marrow
Chromosomes
Cloning
Drug Resistance, Neoplasm
Enzymatic activity
Enzyme inhibitors
Fusion protein
Fusion Proteins, bcr-abl - chemistry
Fusion Proteins, bcr-abl - metabolism
Humans
Imatinib Mesylate
Kinases
Leukemia
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - enzymology
Medicine
Molecular Sequence Data
Mutation
Patients
Philadelphia chromosome
Piperazines
Point mutation
Protein-tyrosine kinase
Pyrimidines - pharmacology
Pyrimidines - therapeutic use
STI571
Los Angeles California
United States > US
California
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Summary:Philadelphia chromosome-associated leukemias are among the most well-understood human malignancies. The importance of BCR-ABL enzymatic activity in the proliferation of the leukemic clone has been confirmed by the high response rates of these leukemias to the ABL-selective tyrosine kinase inhibitor STI571, even in advanced disease phases, which are characterized by increased genetic heterogeneity. Disease relapse has been observed in a subset of patients who had initially responded to STI571. Evidence suggests that BCR-ABL activity is restored in the majority of these cases of acquired resistance. Molecular studies of resistant leukemia cells isolated from patients have implicated BCR-ABL kinase domain point mutation as the most common mechanism of resistance. Additionally, genomic amplification of the BCR-ABL gene can occasionally be detected. This review will highlight mechanisms of STI571 resistance in clinical samples as well as preclinical models.
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ISSN:0950-9232
1476-5594
DOI:10.1038/sj.onc.1206942