The biology of signal transduction inhibition: basic science to novel therapies

Developing drugs to specifically inhibit oncogenes has been a major goal of cancer research for many years. Identifying the appropriate intracellular targets and understanding the signal transduction pathways in which these molecules participate are critical to this process. A large number of the activated oncogenes implicated in the pathogenesis and progression of malignancy are tyrosine kinases. Bcr-Abl, the causative molecular abnormality in chronic myeloid leukemia (CML), is a prototypic oncogenic kinase and an attractive drug target. The tyrosine kinase inhibitor imatinib mesylate (formerly STI571, [Gleevec]; Novartis Pharmaceuticals Corp, East Hanover, NJ) was recently approved for the treatment of CML and provides proof of principle for the strategy of targeted signal transduction inhibition. This drug is effective in the chronic phase of CML, a single gene disorder driven by Bcr-Abl, and in the advanced phases of CML, showing that inhibition of a single oncogene in a multigene disorder also may be of benefit. The success of imatinib mesylate in CML led rapidly to clinical trials in other cancers associated with activation of two other tyrosine kinases known to be sensitive to imatinib mesylate, c-Kit and the platelet-derived growth factor receptor. Gastrointestinal stromal tumors, which have activating mutations in c-Kit, are now also being found to respond to kinase inhibition with the drug. The general approach of specifically targeting activated kinases with small-molecule drugs is likely to be effective in other tumors in the future.