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Spotlight on IMATINIB as a Model for Signal Transduction Inhibitors

Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy

Leukemia volume 16, pages 2190–2196 (2002)Cite this article

Abstract

Selective inhibition of the BCR-ABL tyrosine kinase by imatinib (STI571, Glivec/Gleevec) is a promising new therapeutic strategy in patients with chronic myelogenous leukemia (CML). Despite significant hematologic and cytogenetic responses, resistance occurs, particularly in patients with advanced disease. We sought to determine the underlying mechanisms. Sixty-six patients with CML in myeloid blast crisis (n = 33), lymphoid blast crisis (n = 2), accelerated phase (n = 16), chronic phase (n = 13), and BCR-ABL-positive acute lymphoblastic leukemia (n = 2) resistant to imatinib were investigated. Median duration of imatinib therapy was 148 days (range 6–882). Patients were evaluated for genomic amplification of BCR-ABL, overexpression of BCR-ABL transcripts, clonal karyotypic evolution, and mutations of the imatinib binding site in the BCR-ABL tyrosine kinase domain. Results were as follows: (1) Median levels of BCR-ABL transcripts, were not significantly changed at the time of resistance but 7/55 patients showed a >10-fold increase in BCR-ABL levels; (2) genomic amplification of BCR-ABL was found in 2/32 patients evaluated by fluorescence in situ hybridization; (3) additional chromosomal aberrations were observed in 19/36 patients; (4) point mutations of the ABL tyrosine kinase domain resulting in reactivation of the BCR-ABL tyrosine kinase were detected in 23/66 patients. In conclusion, although the heterogeneous development of imatinib resistance is challenging, the fact that BCR-ABL is active in many resistant patients suggests that the chimeric oncoprotein remains a good therapeutic target. However, patients with clonal evolution are more likely to have BCR-ABL-independent mechanisms of resistance. The observations warrant trials combining imatinib with other agents.

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Acknowledgements

We wish to thank the members of the German CML study group, co-investigators, nursing and research stuff for the excellent cooperation. Clinical and molecular-cytogenetic data have been provided by PD Dr Harald Rieder, University of Marburg, Germany and Prof Dr Werner Linkesch, University of Graz, Austria. The study was supported by a grant from the German Ministry of Education and Research (BMBF), Competence network ‘Acute and chronic leukemias’ – 01 GI9980/6, and the Forschungsfonds der Fakultät für Klinische Medizin Mannheim der Universität Heidelberg.

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Authors and Affiliations

  1. III. Medizinische Universitätsklinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim, Germany

    A Hochhaus, S Kreil, P La Rosée, MC Müller, T Lahaye, B Hanfstein, U Berger & R Hehlmann

  2. Oregon Health and Science University, Portland, OR, USA

    AS Corbin, P La Rosée & BJ Druker

  3. Medizinische Klinik III, Universität München, Germany

    C Schoch

  4. UK and Human Genetics Division, Wessex Regional Genetics Laboratory, Salisbury, University of Southampton, UK

    NCP Cross

  5. Novartis Pharma GmbH, Nürnberg, Germany

    H Gschaidmeier

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  1. A Hochhaus
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Hochhaus, A., Kreil, S., Corbin, A. et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 16, 2190–2196 (2002). https://doi.org/10.1038/sj.leu.2402741

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