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Inhibition of the Bcr-Abl tyrosine kinase as a therapeutic strategy for CML

Oncogene volume 21, pages 8541–8546 (2002)Cite this article

As described in detail throughout this issue, the Bcr-Abl tyrosine kinase is a well-validated therapeutic target in chronic myeloid leukemia (CML). Present in 95% of patients with CML, Bcr-Abl has been demonstrated to be a leukemogenic oncogene in animal studies and is considered the causative molecular abnormality of CML. Bcr-Abl functions as a constitutively activated tyrosine kinase, impacting numerous signaling pathways. However, all of the transforming activities of Bcr-Abl are dependent on its tyrosine kinase activity (Lugo et al., 1990). Thus, an inhibitor of the Bcr-Abl kinase would be predicted to be an effective and selective therapeutic agent for CML.

Compounds that possess inhibitory activity for protein tyrosine kinases were initially isolated from natural sources in the early to mid 1980s. These compounds include the flavinoid, quercetin, the isoflavinoid, genistein, the antibiotic herbimycin A, and erbstatin (Boutin, 1994; Casnellie, 1991; Chang and Geahlen, 1992). Although these compounds can revert cells transformed by tyrosine kinase oncogenes to a non-transformed phenotype, none of these compounds have demonstrated specificity among tyrosine kinases. In the late 1980s, Yaish et al. (1988) synthesized a series of compounds, known as tyrphostins, that were the first compounds to display specificity among tyrosine kinases. One of the tyrphostins, AG1112, inhibits the Abl protein tyrosine kinase, and induces differentiation and death of a Bcr-Abl-positive, erythroid blast crisis, CML cell line, K562 (Anafi et al., 1993; Kaur et al., 1994). Similar data for induction of K562 differentiation has been obtained with genistein, herbimycin A, and erbstatin (Honma et al., 1989, 1990; Kawada et al., 1993).

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Acknowledgements

Dr Druker is supported by grants from the National Cancer Institute, The Leukemia and Lymphoma Society, Burroughs Wellcome Fund, T.J. Martell Foundation, and the Doris Duke Charitable Foundation.

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  1. Oregon Health & Science University Cancer Institute, L592, 3181 SW Sam Jackson Park Road, Portland, 97239, Oregon, OR, USA

    Brian J Druker

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Druker, B. Inhibition of the Bcr-Abl tyrosine kinase as a therapeutic strategy for CML. Oncogene 21, 8541–8546 (2002). https://doi.org/10.1038/sj.onc.1206081

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