Geranylgeranyltransferase I as a target for anti-cancer drugs.

Abstract

Posttranslational modification is critical for the function of the gene products of ras oncogenes, which are frequently mutated in cancer. Ras proteins are modified by farnesyltransferase (FTase), but many related small GTPases that also end in a CAAX motif (where C is cysteine, A is often an aliphatic amino acid, and X is any amino acid) are modified by a closely related enzyme known as geranylgeranyltransferase type I (GGTase-I). Accordingly, inhibitors for both of these enzymes have been developed, and those active against FTase are in clinical trials. In this issue of the JCI, Sjogren et al. report the development of a mouse strain homozygous for a conditional allele of the gene that encodes GGTase-I (see the related article beginning on page 1294). They found that ablation of the GGTase-I-encoding gene in cells destined to produce lung tumors driven by oncogenic K-Ras resulted in delayed onset and decreased severity of disease, validating in a genetic model the theory that GGTase-I is a good target for anti-cancer drug development.