Farnesyltransferase inhibitors define a role for RhoB in controlling neoplastic pathophysiology

A long-standing goal in cancer research is to identify cellular functions t hat have selective roles in regulating neoplastic pathophysiology. Farnesyl transferase inhibitors (FTIs) are a novel class of cancer chemotherapeutics which have little effect on normal cell physiology but which inhibit or re verse malignant cell phenotypes, FTIs were originally developed as a strate gy to inhibit oncogenic Pas, the activity of which depends upon posttransla tional farnesylation. However, recent work indicates the antineoplastic eff ects of FTIs are not linked to Pas inhibition but instead to alteration of RhoB, a small GTPase of the Rho family of cytoskeletal regulators that cont rols trafficking of cell surface receptors. Rho proteins integrate signals from integrins and cytokine receptors with cell shape via the actin cytoske leton. A connection between FTIs and Rho alteration is interesting given th at histological differences have long been used to define clinical cancer. RhoB is dispensable for normal cell growth and differentiation in mice. Thu s, research into the antineoplastic effects of FTIs has led to the identifi cation of a function(s) that is unnecessary for normal cell physiology but crucial for controlling malignant phenotypes.