©2003 Landes Bioscience. Not for distribution. [Cancer Biology & Therapy 1:6, 599-606, November/December 2002]; ©2002 Landes Bioscience www.landesbioscience.com Cancer Biology & Therapy 599 Adrienne D. Cox 1,2,3 Channing J. Der 1,3, * 1 University of North Carolina at Chapel Hill; Lineberger Comprehensive Cancer Center; Departments of 2 Radiation Oncology; and 3 Pharmacology; Chapel Hill, North Carolina USA *Correspondence to:C. J. Der; University of North Carolina at Chapel Hill; Lineberger Comprehensive Cancer Center; CB #7295; 102 Mason Farm Road; Chapel Hill, North Carolina 27599-7295 USA; Tel.: 919.966.5634; Fax: 919.966.0162; Email: cjder@med.unc.edu Submitted: 11/18/02; Accepted 11/18/02 Previously published online as a CB&T “Paper in Press” at: http://landesbioscience.com/journals/cbt/ KEY WORDS Ras, Mitogen-activated protein kinase, Farnesyltransferase inhibitors, Signal transduction Review Ras Family Signaling Therapeutic Targeting ABSTRACT Mutationally activated and oncogenic versions of the ras genes were first identified in human tumors in 1982. This discovery prompted great interest in the development of anti-Ras strategies as novel, target-based approaches for cancer treatment. The three human ras genes represent the most frequently mutated oncogenes in human cancers. Consequently, a considerable research effort has been made to define the function of Ras in normal and neoplastic cells and to target Ras for cancer treatment. Among the anti-Ras strategies that are under evaluation in the clinic are pharmacologic inhibitors designed to prevent: (1) association with the plasma membrane (farnesyltransferase inhibitors), (2) downstream signaling (Raf and MEK protein kinase inhibitors), (3) autocrine growth factor signaling (EGF receptor inhibitors), or (4) gene expression (H-ras and c-raf-1). Although a number of these inhibitors have demonstrated potent anti-tumor activities in preclinical models, phase I-III clinical trials have revealed unexpected complexities in Ras function and in the clinical development of target-based therapies. We review the current status of anti-Ras drug development, issues that have complicated their progression to the clinic, and possible future strategies for targeting Ras. INTRODUCTION—RAS AS A TARGET FOR ANTI-CANCER TREATMENT Overall, mutated ras alleles are found in 30% of all human cancers, with high frequencies seen in cancers with limited therapeutic options and poor survival, including cancers of the lung and pancreas (30–90%). 1 Ras is also activated in cancer cells by other mechanisms, including by perturbations in other signaling components, such as receptor tyrosine kinases (RTKs). 2 In particular, the epidermal growth factor receptor (EGFR) is overexpressed or mutationally activated in many human cancers, and hyperactivation of EGFR tyrosine kinase activity in turn causes persistent activation of Ras and Ras-mediated signaling. Hence, the involvement of Ras in cancers extends significantly beyond those where ras is activated by mutation. That Ras can play an essential role in tumor maintenance and is therefore an appropriate target for anticancer therapy is clear. 3 Further, the ability of oncogenic Ras to reduce the expression of tumor suppressor genes such as p16 via promoter methylation 4 suggests that anti-Ras drugs may also provide anti-tumor benefits by reactivation of lost tumor suppressor function. The rational development of anti-Ras drugs requires understanding the function of Ras proteins in normal cells and how this function is usurped in cancer cells. Intensive basic research studies have achieved much of this goal and our understanding of Ras function is now immense, albeit still far from complete. 2 We presently have a detailed picture of the role of Ras in signal transduction and the mechanisms by which Ras regulates cell proliferation, survival, and differentiation. This information has guided current strategies designed to antagonize different facets of Ras important for its oncogenic function: association with the inner face of the plasma membrane, activation of a protein kinase cascade, induction of growth factor production, and gene expression. These approaches are under evaluation in clinical trials and many more are under investigation in preclinical studies. However, despite two decades of effort, no anti-Ras strategies have yet reached common clinical practice. Are the current approaches the wrong ones? Is Ras a poor target? Or is success just around the corner? These questions cannot be answered yet, partly because such development has been complicated by two issues. First, while our knowledge of Ras function is now considerable, it has become clear that Ras biochemistry and biology is much more complex than had been imagined, and we still remain ignorant of many aspects of Ras function. Second, the clinical development of target-based drugs for cancer