Inhibiting signal transduction: Recent advances in the development of receptor tyrosine kinase and Ras inhibitors

Since aberrant cell signaling is implicated in the initiation, growth, and progression of cancer, proteins involved in signal transduction are rational therapeutic targets. Receptor tyrosine kinases (RTK) and Ras oncoprotein are examples of critical signaling proteins that mediate the processes of cellular growth and differentiation. Agents presently being evaluated as inhibitors of signal transduction include both natural and synthetic compounds, monoclonal antibodies, and antisense oligonucleotides. Preclinical studies of compounds which inhibit RTK and Ras have shown that these targets can be blocked, while side effects in animal models are minimal. Early clinical trials reveal that, in general, treatment with these compounds is both feasible and tolerable. However, many issues about STI remain unresolved including how to optimize schedule, how long to continue treatment, specific mechanisms of action, and how to optimize combinations of STI with standard therapeutic modalities. Addressing these issues may require a shift ill the traditional paradigm of drug development, as conventional endpoints may not adequately capture the potential benefits from agents believed to act in a cytostatic vs. cytotoxic. c manner. This review will discuss the rationale and application of inhibiting signal transduction using inhibitors of RTK and Ras as prototypes of this class of agents.