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Mechanisms of resistance to STI571 in Philadelphia chromosome-associated leukemias

Oncogene volume 22, pages 7389–7395 (2003)Cite this article

Abstract

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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Acknowledgements

We thank Phuong Huynh for assistance with manuscript preparation. NPS and CLS are supported by awards from the Leukemia and Lymphoma Society. CLS is a Doris Duke Distinguished Clinical Scientist.

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Authors and Affiliations

  1. Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, 90095, CA, USA

    Neil P Shah & Charles L Sawyers

  2. Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, 90095, CA, USA

    Charles L Sawyers

  3. Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, 90095, CA, USA

    Charles L Sawyers

  4. Department of Medical and Molecular Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, 90095, CA, USA

    Charles L Sawyers

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Correspondence to Charles L Sawyers.

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Shah, N., Sawyers, C. Mechanisms of resistance to STI571 in Philadelphia chromosome-associated leukemias. Oncogene 22, 7389–7395 (2003). https://doi.org/10.1038/sj.onc.1206942

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