Treatment of H-Ras transgenic mice with the geranylgeranyltransferase I (GGTase I) inhibitor, GGTI-2154, results not only in halting the growth of aggressive breast tumors but actually in the regression (54 +/− 3%) of all 19 tumors analyzed. The farnesyltransferase (FTase) inhibitor, FTI-2148, induces an average of 87 +/− 3% regression in the 13 tumors analyzed. GGTase I, but not FTase, is inhibited in breast tumors following treatment with GGTI-2154, while in tumors from mice treated with FTI-2148, only FTase is inhibited. The processing of the geranylgeranylated proteins RhoA, Rap1 and R-Ras, but not the farnesylated proteins H-Ras and HDJ-2, is inhibited in tumors obtained from mice treated with GGTI-2154. GGTI-2154 and FTI-2148 suppress constitutively activated phospho Erk1/2 and phospho-Akt, induce apoptosis, and differentiation towards ductolobular breast epithelium. The data demonstrate that geranylgeranylated proteins are critical in H-Ras oncogenesis in vivo and gives strong support for GGTase I as a target for anticancer drug discovery.

[Proc Amer Assoc Cancer Res, Volume 45, 2004]