Farnesyltransferase inhibitors define a role for RhoB in controlling neoplastic pathophysiology

Abstract

A long-standing goal in cancer research is to identify cellular functions that have selective roles in regulating neoplastic pathophysiology. Farnesyltransferase inhibitors (FTIs) are a novel class of cancer chemotherapeutics which have little effect on normal cell physiology but which inhibit or reverse malignant cell phenotypes. FTIs were originally developed as a strategy to inhibit oncogenic Ras, the activity of which depends upon posttranslational farnesylation. However, recent work indicates the antineoplastic effects of FTIs are not linked to Ras inhibition but instead to alteration of RhoB, a small GTPase of the Rho family of cytoskeletal regulators that controls trafficking of cell surface receptors. Rho proteins integrate signals from integrins and cytokine receptors with cell shape via the actin cytoskeleton. A connection between FTIs and Rho alteration is interesting given that histological differences have long been used to define clinical cancer. RhoB is dispensable for normal cell growth and differentiation in mice. Thus, research into the antineoplastic effects of FTIs has led to the identification of a function(s) that is unnecessary for normal cell physiology but crucial for controlling malignant phenotypes.