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  • Commentary and Mini Review
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Commentary and Mini-Review

Small-molecule inhibitors of signal transduction pathways in leukemia therapeutics: how to assess selectivity for malignant signals

Leukemia volume 17, pages 1759–1761 (2003)Cite this article

This invited commentary is addressed to the paper of Shelton et al1 published in this issue of Leukemia. The intracellular signaling pathways that control cell proliferation present attractive targets for the design of therapeutic agents to treat cancer. In between the growth factor receptors that are found on the cell surface and the nuclear events that are involved in regulating cell proliferation and apoptosis, lie two important signal transduction pathways: the MAPK and the PI3K cascades. In many cancers, aberrant activation of these pathways can occur as a result of mutation of a gene encoding a component signaling protein within the pathway. This leads to constitutive activation of the protein and a consequent inappropriate transmission of a continual signal for cell proliferation. For example, mutation and retroviral capture of the gene encoding the serine/threonine protein kinase-B also known as c-Akt (PKB/Akt) in the PI3K pathway produced the oncogene v-akt. Similarly, mutation and retroviral capture of the kinase c-Raf in the MAPK cascade produced the oncogene v-raf.

Small-molecule inhibitors of the MAPK and PI3K pathways should, in principle, be able to block the effects of these oncogenes and thus inhibit cell proliferation and promote apoptosis of transformed cells. However, there is a problem. Both the MAPK and PI3K are involved in the regulation of many cellular processes in normal cells. So how can the therapeutic potential of small-molecule inhibitors be evaluated relative to their potentially toxic effects on normal cells? Progress towards resolving this issue is presented in the paper by Shelton et al1 published in this issue of Leukemia.

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  1. Department of Pathology, Anatomy and Cell Biology, Jefferson Medical College, Jefferson Alumni Hall, Philadelphia, PA, USA

    M K White

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White, M. Small-molecule inhibitors of signal transduction pathways in leukemia therapeutics: how to assess selectivity for malignant signals. Leukemia 17, 1759–1761 (2003). https://doi.org/10.1038/sj.leu.2403053

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