Searching new targets for anticancer drug design: the families of Ras and Rho GTPases and their effectors

Abstract

The Ras superfamily of low-molecular-weight GTPases are proteins that, in response to diverse stimuli, control key cellular processes such as cell growth and development, apoptosis, lipid metabolism, cytoarchitecture, membrane trafficking, and transcriptional regulation. More than 100 genes of this superfamily grouped in six subfamilies have been described so far, pointing to the complexities and specificities of their cellular functions. Dysregulation of members of at least two of these families (the Ras and the Rho families) is involved in the events that lead to the uncontrolled proliferation and invasiveness of human tumors. In recent years, the cloning and characterization of downstream effectors for Ras and Rho proteins have given crucial clues to the specific pathways that lead to aberrant cellular growth and ultimately to tumorigenesis. A direct link between the functions of some of these effectors with the appearance of transformed cells and their ability to proliferate and invade surrounding tissues has been made. Accordingly, drugs that specifically alter their functions display antineoplasic properties, and some of these drugs are already under clinical trials. In this review, we survey the progress made in understanding the underlying molecular connections between carcinogenesis and the specific cellular functions elicited by some of these effectors. We also discuss new drugs with antineoplastic or antimetastatic activity that are targeted to specific effectors for Ras or Rho proteins.