The ras family of proto-oncogenes are upstream mediators of several essential cellular signal transduction pathways involved in cell proliferation and survival. Point mutations of ras oncogenes result in constitutively active Ras and have been shown to be oncogenic. However, ras activation can occur in the absence of ras mutations secondary to upstream receptor activation. The first important step in Ras activation is farnesylation by farnesyl
transferase, and inhibitors of this
enzyme have been demonstrated to inhibit Ras signaling, and have anti-
tumor effects. However, it is now clear that farnesyl
transferase inhibitors (FTIs) have activity independent of Ras, most likely due to effects on prenylated
proteins downstream of Ras, which explains their activity in several
malignancies, including
breast cancer, where ras mutations are rare. Several FTIs are in clinical development for the treatment of solid
tumors. Preclinical evidence suggests that FTIs can inhibit breast
cancers in vitro and in vivo, and a phase II trial of the FTI,
R115777, in patients with advanced
breast cancer produced encouraging results. Based on prior successful outcomes with agents targeting the
estrogen and
epidermal growth factor receptor pathways in
breast cancer, the FTIs, used alone or more likely with other agents, may be the next exciting targeted
therapy in
breast cancer.