Inhibitors of the ras oncogene as therapeutic targets

Advances in our understanding of the molecular pathways and genetic mutations that control tumor cell proliferation and metastasis present an opportunity to develop novel, mechanism-based therapeutic strategies. Ras mutations are the most frequently activated oncogenes in human tumors, with over 30% expressing ras mutations. Molecular dissection of the signaling pathway and the mechanisms of ras anchorage, post-translational modification, and downstream effector signaling of ras now under intensive investigation will help us to design additional methods for ras-directed therapy in an effort to reach an optimal treatment for human tumors that will most likely comprise a combination of modalities targeted at the different underlying genetic defects. The successes and limitations of ras-targeted therapies must be viewed in light of the increasing understanding of the complexity of the ras-signaling pathway. Only now are we beginning to discover the many functions of this integrated pathway, such as the differences between the actions of various ras isoforms that may affect our choice of therapeutic approach. Many of these Ras therapeutic targets have shown success in preclinical studies, and some have shown efficacy in clinical trials with minimal toxicities. Compounds that block ras-transforming activity without affecting normal ras function seem more attractive for the future development of ras-targeted therapy. FTIs may partially fulfill such requirements. Based on their specific, novel, and mechanism-based action; minimal toxicity; and encouraging responses in clinical trials, the development of Ras therapeutic targets as single agents or in combination with conventional chemotherapy and radiotherapy should be pursued.