Farnesyl transferase inhibitors as anticancer agents

doi:10.1016/S0959-8049(02)00166-1

European Journal of Cancer

Volume 38, Issue 13, September 2002, Pages 1685-1700

https://doi.org/10.1016/S0959-8049(02)00166-1 Get rights and content

Abstract

Protein farnesylation catalysed by the enzyme farnesyl protein transferase involves the addition of a 15-carbon farnesyl group to conserved amino acid residues at the carboxyl terminus of certain proteins. Protein substrates of farnesyl transferase include several G-proteins, which are critical intermediates of cell signalling and cytoskeletal organisation such as Ras, Rho, PxF and lamins A and B. Activated Ras proteins trigger a cascade of phosphorylation events through sequential activation of the PI3 kinase/AKT pathway, which is critical for cell survival, and the Raf/Mek/Erk kinase pathway that has been implicated in cell proliferation. Ras mutations which encode for constitutively activated proteins are found in 30% of human cancers. Because farnesylation of Ras is required for its transforming and proliferative activity, the farnesyl protein transferase inhibitors were designed as anticancer agents to abrogate Ras function. However, current evidence suggests that the anticancer activity of the farnesyl transferase inhibitors may not be simply due to Ras inhibition. This review will discuss available clinical data on three of these agents that are currently undergoing clinical trials.

Introduction

Advances in molecular biology over the past decade have identified a number of novel targets for cancer therapy. One such target is the enzyme farnesyl protein transferase (FT), which catalyses a key step in the addition of an aliphatic isoprenoid side chain to a number of proteins. A novel class of antineoplastic agents, the farnesyl transferase inhibitors (FTIs), have recently been developed to specifically inhibit FT. These inhibitors were designed to target Ras, a G-protein with 4 isoforms (H-, N- and K-RasA/K-RasB) mutated in a large number of cancers, which requires prenylation for function [1]. However, it has become clear in many instances that Ras may not be the critical target of FTIs. For instance, in human tumour cell lines, the antitumour activity of FTIs does not correlate with a mutated Ras status 2, 3. The findings that K- and N-Ras can be alternatively prenylated by geranylgeranyl protein transferase (GGT) also argues against Ras as the target, as preclinical models bearing these mutations are sensitive to FTI treatment 4, 5, 6, 7. To date, more than a hundred polypeptides possessing a ‘CAAX’ (tetrapeptide motif, where C is cysteine, A is any alphatic amino acid and X is serine, leucine, glutamine or methironine) sequence that can potentially be farnesylated have been identified [8]. Theoretically, the inhibition of farnesylation of any of these polypeptides could result in the antiproliferative effects of the FTIs in human tumours.

Despite uncertainty about the true target of FTIs, these agents demonstrate anticancer activity as single agents and in combination with standard cytotoxic chemotherapy 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18. In addition, FTIs synergise with gamma irradiation, and may have a role in chemoprevention 19, 20, 21. This review will focus on the FTIs that are currently undergoing clinical investigations. Published results of these clinical trials will be discussed. Recent investigations into the targets of FTIs will also be discussed.

Section snippets

Farnesyl protein transferase

FT is a heterodimeric metalloenzyme whose activity is dependent on magnesium and zinc, the latter of which is required for coordination of the farnesyl-accepting cysteine of the target protein and the active site of the enzyme [22]. FT catalyses the addition of a 15-carbon isoprenyl farnesyl moiety, to the carboxy terminus of proteins containing the peptide target motif ‘CAAX’. Similarly, the related protein geranylgeranyl transferase type I (GGT-1) catalyses the addition of a 20-carbon

Protein farnesylation

The addition of a farnesyl group to conserved amino acid residues at the carboxy terminus is necessary for the proper functioning of many farnesylated proteins. The farnesylation reaction is part of a series of modifications necessary for plasma membrane association of various proteins (Fig. 1). While it is generally believed that prenylation confers a hydrophobic core necessary to anchor proteins to cell membranes, more investigation is needed to understand the entire spectrum of function that

Mechanism of FTI cytotoxicity

More than 70% of cancer cell lines have shown sensitivity to FTI treatment. FTIs inhibit the anchorage-independent growth of this large variety of transformed cell lines 2, 39, 40, 41. In addition, while FTIs clearly abrogate FT activity both in cultured cell lines and in surrogate tissue 9, 15 or tumour cells 9, 15 from patients, it has become increasingly clear that FTIs do not target only Ras, but may have other protein targets as well. As mentioned earlier in the introduction, there is no

Preclinical/clinical studies

Three FTIs (Fig. 3) are undergoing clinical testing currently as monotherapy, and in combination with standard cytotoxic agents (Table 2). An additional agent, L-778,123, was introduced into the clinic, but its further development has been halted due to toxicity. At least three other compounds are in late preclinical testing and may be introduced into clinical trials shortly.

FTIs in combination with ionising radiation

Ras oncogenes have been reported to confer resistance to ionising radiation 93, 94. Since the FTIs were presumed to be inhibiting ras proteins, their role as radiosensitising agents, have been evaluated. In spite of the uncertainty surrounding their ras inhibitory effects, the FTIs have been shown to synergise with gamma radiation in preclinical models.

Because activated H-ras expression had been shown to markedly increase radiation resistance in some transformed cells and FTI-277 was shown to

Conclusions

FTIs are a promising class of novel antineoplastic agents. Although initially designed as anti-Ras agents, mounting evidence indicates that other farnesylated targets are involved in the cytotoxic effects of these agents. Identification of the critical protein target(s) of FTIs is currently an active area of research 2, 38, 60, 61, 62, 74, 76, 100, 101. The FTIs are generally well tolerated at clinically effective doses [102]. Some of their toxicities, such as nausea, vomiting and diarrhoea,

Acknowledgements

A.A.A. is a recipient of a Research Scholar Grant (RSG-01–155–01-CCE) from the American Cancer Society. The authors wish to thank Mrs Gail Prechel for expert secretarial assistance.

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ReviewFarnesyl transferase inhibitors as anticancer agents

Abstract

Introduction

Section snippets

Farnesyl protein transferase

Protein farnesylation

Mechanism of FTI cytotoxicity

Preclinical/clinical studies

FTIs in combination with ionising radiation

Conclusions

Acknowledgements

J. Biol. Chem.

J. Biol. Chem.

Blood

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Cell

Genomics

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Exp. Cell Res.

J. Biol. Chem.

Blood

Isoprenoid addition to Ras protein is the critical modification for its membrane association and transforming activity

Proc. Natl. Acad. Sci. USA

A peptidomimetic inhibitor of farnesyl:protein transferase blocks the anchorage-dependent and-independent growth of human tumor cell lines

Cancer Res.

Inhibition of human tumor xenograft growth by treatment with the farnesyl transferase inhibitor B956

Cancer Res.

Both farnesyltransferase and geranylgeranyltransferase I inhibitors are required for inhibition of oncogenic K-Ras prenylation but each alone is sufficient to suppress human tumor growth in nude mouse xenografts

Oncogene

Inhibition of the prenylation of K-Ras, but not H- or N-Ras, is highly resistant to CAAX peptidomimetics and requires both a farnesyltransferase and a geranylgeranyltransferase I inhibitor in human tumor cell lines

Oncogene

A phase II study of the farnesyl transferase inhibitor R115777 in patients with advanced breast cancer

Proc. Annu. Meet. Am. Soc. Clin. Oncol.

Induction therapy with SCH 66336, a farnesyltransferase inhibitor, in squamous cell carcinoma (SCC) of the head and neck

Proc. Annu. Meet. Am. Soc. Clin. Oncol.

A phase I, clinical and pharmacokinetic (PK) trial of the farnesyl transferase inhibitor (FTI) R115777+docetaxela promising combination in patients (PTS) with solid tumors

Proc. Annu. Meet. Am. Soc. Clin. Oncol.

Phase I and pharmacologic study with the novel farnesyl transferase inhibitor (FTI) R115777

Proc. Annu. Meet. Am. Soc. Clin. Oncol.

Use of farnesyl transferase inhibitor R115777 in relapsed and refractory acute leukemias: preliminary results of a phase I trial

Proc. Annu. Meet. Am. Soc. Clin. Oncol.

A phase I pharmacokinetic (PK) and biological study of the farnesyl transferase inhibitor (FTI) R115777 and capecitabine in patients (PTS) with advanced solid malignancies

Proc. Annu. Meet. Am. Soc. Clin. Oncol.

A Phase I trial of the farnesyl transferase inhibitor SCH66336evidence for biological and clinical activity

Cancer Res.

Phase I pharmacokinetic trial of the farnesyl transferase inhibitor SCH66336 plus gemcitabine in advanced cancers

Proc. Annu. Meet. Am. Soc. Clin. Oncol.

Phase I study of farnesyl transferase inhibitor (FTI) SCH66336 with paclitaxel in solid tumors: dose finding, pharmacokinetics, efficacy/safety

Proc. Annu. Meet. Am. Soc. Clin. Oncol.

A phase I/II study of the farnesyl transferase inhibitor (FTI) SCH66336 with paclitaxel in patients with solid tumors

Proc. Annu. Meet. Am. Assoc. Cancer Res.

The farnesyltransferase inhibitor FTI-277 suppresses the 24-kDa FGF2-induced radioresistance in HeLa cells expressing wild-type RAS

Radiat. Res.

Inhibiting Ras prenylation increases the radiosensitivity of human tumor cell lines with activating mutations of ras oncogenes

Cancer Res.

The farnesyltransferase inhibitor FTI-277 radiosensitizes H-ras- transformed rat embryo fibroblasts

Cancer Res.

Enzymatic modification of proteins with a geranylgeranyl isoprenoid

Proc. Natl. Acad. Sci. USA

p21ras is modified by a farnesyl isoprenoid

Proc. Natl. Acad. Sci. USA

Sequence requirement for peptide recognition by rat brain p21ras protein farnesyltransferase

Proc. Natl. Acad. Sci. USA

The prenylation of proteins

Bioessays

Crystal structure of farnesyl protein transferase complexed with a CaaX peptide and farnesyl diphosphate analogue

Biochemistry

Tricyclic farnesyl protein transferase inhibitorscrystallographic and calorimetric studies of structure-activity relationships

J. Med. Chem.

Review
Farnesyl transferase inhibitors as anticancer agents