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 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.
Department of Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA 90095, USA.
Neil P
NP
Shah
Charles L
CL
Sawyers
D000595:Amino Acid Sequence; D000818:Animals; D001549:Benzamides; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology; D008969:Molecular Sequence Data; D010879:Piperazines; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use*
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl