Cancer therapy targeted at cellular signal transduction mechanisms: strategies, clinical results, and unresolved issues.

Much effort is currently being spent on developing anticancer drugs targeted at cellular signal transduction mechanisms, and several signal inhibitors have also been introduced into clinical practice. The rationale for such therapy is the realization that, in general, oncogenes and tumour suppressor genes encode proteins that are mutated or dysregulated forms of key components in major regulatory pathways. However, while we have witnessed striking clinical effects in certain malignancies, as in the treatment of chronic myelogeneous leukemia, the results in many other cancers have been rather disappointing, and this has raised the question of whether major advances can realistically be expected by the use of signal-targeted therapies on a broad scale. Here we briefly review the cellular and molecular basis for treatment with pharmacological signal inhibitors and the clinical experience with their use in different malignancies. We also discuss general strategies to improve the treatment, including approaches to the problem of resistance development. Clinical results vary greatly, from little or no treatment success in some cancers to an increasing number of examples of very promising responses. Progress has primarily been achieved in those malignancies and subsets of patients where the underlying molecular mechanisms have been explored in detail and the targets have been well defined. In conclusion, it is likely that novel signal-directed approaches will lead to further important advances in cancer therapy, but this will require continued efforts to identify targets that are oncogenic determinants, and systematic work to select patients for more individualized therapies.