Antitumor Efficacy of a Farnesyltransferase Inhibitor in Transgenic Mice

The ras genes, Harvey (H-), Kirsten (K-), and N-ras were among the first oncogenes found to be mutated in human cancers (1). In particular, a splice variant of Ki-ras, termed “Ki4B-ras,” is the most commonly mutated form of ras found to be altered in the majority of colon and pancreatic carcinomas. Because solid tumors are often the most difficult to treat clinically, in academic and pharmaceutical settings, great effort has been placed on developing inhibitors to the function of the products of ras genes, the Ras proteins. Many of the early efforts to modify Ras GTP binding, GTPase activity, or Ras interactions with putative effector molecules such as GAP, neurofibromin, or Raf were not successful (2). In 1989, however, new insights were realized when the chemical modifications were identified that convert Ras from a biologically inactive precursor protein in the cytoplasm into a mature and biologically active protein in the plasma membrane (3,4). The key modification, farnesylation of Cys on the Ras C-terminal CAAX sequence (C, Cys; a, aliphatic amino acid; X, another amino acid) is catalyzed by protein farnesyltransferase (FTase). FTase has afforded a target for drug discovery that has yielded compounds with properties appropriate for clinical testing (5–7).