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  • Molecular Targets For Therapy (MTT)
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Molecular Targets for Therapy (MTT)

Efficacy of dual-specific Bcr-Abl and Src-family kinase inhibitors in cells sensitive and resistant to imatinib mesylate

Leukemia volume 18, pages 1352–1356 (2004)Cite this article

Abstract

Monotherapy of chronic myeloid leukemia (CML) with imatinib mesylate has been cast into shadow by the evolution of clinical resistance during therapy. Resistance to imatinib can arise by multiple mechanisms including amplification or mutation of Bcr-Abl, and continuity of imatinib therapy is probably a poor option for either of these patient groups. Recently, however, a structurally distinct new class of drugs, the pyrido[2,3-d]pyrimidines, has been described, and these compounds are predicted to make different molecular contacts in the Abl kinase domain. These drugs potently target both the Bcr-Abl and Src-family kinase activities, both of which are thought to be relevant to survival of the leukemic cell. We asked whether these drugs could selectively induce cell death in murine cell line models of CML cells sensitive and resistant to imatinib by different mechanisms. We show that whereas the pyrido[2,3-d] pyrimidines are indeed highly potent in suppressing proliferation of Bcr-Abl-overexpressing imatinib-resistant cells, they are almost completely ineffective against cells expressing the T315I mutant. This implies that despite structural differences from imatinib, these drugs are unlikely to be useful in patients expressing this mutant Bcr-Abl protein, but may be effective in cases where selection of cells overexpressing the oncoprotein leads to refractoriness to imatinib.

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Acknowledgements

We are grateful to Dr Elisabeth Buchdunger (Novartis Pharma, Basel, Switzerland) for the gift of imatinib mesylate, and to Dr Charles Chuah (Department of Haematology, Imperial College) for technical help. This work was supported by grants from the Leukaemia Research Fund, UK (AJT, SB, DJB, JMG, JVM); NCI Grants CA64593 and CA08748; The Albert C Bostwick Foundation, Mr William H Goodwin and Mrs Alice Goodwin and the Commonwealth Cancer Foundation for Research, The Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center, New York, The Enid A Haupt Charitable Trust, The Leukemia & Lymphoma Society, The United Leukemia Fund, The Westvaco Corporation and MeadWestvaco (DRV, WGB, BMC); and the Association pour la recherche sur le cancer and Fondation de la recherche medicale, France (FXM).

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Authors and Affiliations

  1. Department of Haematology, Imperial College London, Hammersmith Hospital, London, UK

    A J Tipping, S Baluch, D J Barnes, J M Goldman & J V Melo

  2. Memorial Sloan-Kettering Cancer Center, New York, USA

    D R Veach, B M Clarkson & W G Bornmann

  3. Laboratoire Greffe de Moelle, Université Victor Segalen, Bordeaux, France

    F X Mahon

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  1. A J Tipping
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Tipping, A., Baluch, S., Barnes, D. et al. Efficacy of dual-specific Bcr-Abl and Src-family kinase inhibitors in cells sensitive and resistant to imatinib mesylate. Leukemia 18, 1352–1356 (2004). https://doi.org/10.1038/sj.leu.2403416

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