Farnesyl transferase inhibitors: the next targeted therapies for breast cancer?

Abstract

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.

Target-based therapies in breast cancer: current status and future perspectives

“…However, many potential substrates, independent of Ras, have been identified for farnesyl transferase inhibitors (FTIs), such as lamin A and human perioxisomal farnesylated protein, both of which have been used as surrogate markers of farnesylation, RhoB, cyclic guanosine monophosphate phosphodiesterase a, rhodopsin kinase and the g subunit of the retinal protein, transducin (O'Regan & Khuri 2004). The oral FTIs currently in clinical development are tipifarnib, lonafarnib and AZD3409 (Table 1).…”

“…Phase I studies of tipifarnib showed that continuous dosing was associated with severe toxicities, such as diarrhea, nausea, vomiting, renal dysfunction, and myelosuppression (O'Regan & Khuri 2004). A phase II study evaluated the activity of tipifarnib, as single agent, in endocrine-and/or chemotherapy-resistant patients with metastatic breast cancer .…”

Endpoint of Cancer Treatment: Targeted Therapies

“…The Ras family of proto-oncogenes are upstream mediators of several essential cellular signal transduction pathways and, as such, provide a rational target for the treatment of malignancies (O'Regan and Khuri, 2004). Inhibitors of the enzyme farnesyl protein transferase prevent a key step in the post-translational processing of the RAS protein, and were developed initially as a therapeutic strategy to inhibit cell signalling in RAStransformed cells (Johnston, 2001).…”

Combination therapy with aromatase inhibitors: the next era of breast cancer treatment?

“…The ras proto-oncogene can activate downstream TK substrates (e.g., MAPK, MAPK/ERK kinase (MEK)) that influence cell proliferation, survival and apoptosis and has been implicated in breast cancer (O'Regan and Khuri, 2004). Farnesyl transferase inhibitors (e.g., tipifarnib, lonafarnib) were developed to inhibit tumour growth by blocking farnesylation, the first step in ras activation.…”

“…Both in vitro and in vivo studies have shown that tipifarnib inhibits the growth of MCF-7 breast cancer tumours (O'Regan and Khuri, 2004), and a subsequent phase II study reported clinical benefit in 24% of women with endocrine-resistant metastatic breast cancer .…”