Kinase components of the Ras-MAPK signaling cascade as potential targets for therapeutic intervention

The Ras-MAPK signaling cascade plays a role of central importance in cellular growth, proliferation and survival. Activation of this pathway by stimuli from hormones and growth factor receptors at the cell surface results in the transmission of signals to various transcription factors within the nucleus that mediate these processes. The downstream effector of Ras is Raf, a serine/threonine kinase. Upon activation by Ras, Raf phosphorylates the serine residues of MEK1 and MEK2, which in turn phosphorylate the MAPK family proteins ERK1 and ERK2. Activated ERK1 and ERK2 translocate to the nucleus, stimulating growth and proliferative processes by activation of various substrates. Aberrant signaling within this pathway has been associated with the formation of human tumors, making the kinase components of the Ras-MAPK signaling cascade attractive targets for pharmaceutical intervention. This review describes a variety of agents that have been identified as inhibitors of the kinase components of this signaling pathway - natural products, synthetic compounds, as well as antisense oligonucleotides. Preclinical studies have demonstrated that certain inhibitors are well tolerated in mammals, and can effectively inhibit the growth of selected human tumor cell lines. Several Raf and MEK kinase inhibitors have been advanced to clinical trials, where preliminary evidence of efficacy has been noted. Studies have been initiated to evaluate these agents in combination with cytotoxic drugs. The work described in this review suggests that this area of research has been fruitful, providing several potential anticancer agents currently under investigation.