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Targeting protein prenylation for cancer therapy

Key Points

  • Post-translational modifications with the lipids farnesyl or geranylgeranyl (together referred to as prenyl) are catalysed by farnesyltransferase (FT) or geranylgeranyltransferase 1 (GGT1) and are required for the cellular localization, function and cancer-causing activities of some proteins. Among the hundreds of proteins that are estimated to be prenylated most are either exclusively farnesylated (for example, HRAS and RAS homologue enriched in brain (RHEB)) or geranylgeranylated (for example, RHOA, RHOC, RALA and RALB); some are both farnesylated and geranylgeranylated (RHOB), and others are naturally farnesylated but become geranylgeranylated when FT is inhibited (for example, KRAS and NRAS).

  • These and other important observations prompted the design and development of inhibitors of FT (FTIs) and GGT1 (GGTIs) as potential anticancer drugs. Several FTIs have been tested clinically but only one GGTI has recently entered clinical trials.

  • Further validation of FT and GGT1 as anticancer drug targets was recently provided by genetic mouse models: conditional loss of FT and/or GGT1 hampers mutant KRAS-induced tumorigenesis and extends the lifespan of mice.

  • FTI treatment results in the reversal of several hallmarks of cancer, including mitotic arrest at prometaphase, induction of apoptosis, inhibition of anchorage-dependent and anchorage-independent growth, invasion, angiogenesis and tumour growth, as well as induction of tumour regression in animal models. These effects seem to be mediated by interference with aberrant signal transduction pathways such as RAF–MEK–ERK, PI3K–AKT, and other oncogenic and survival pathways.

  • GGTI treatment also results in the reversal of the cancer hallmarks mentioned above except that they block cells in the G1 phase of the cell cycle, and this seems to be owing to their ability to induce the accumulation of the cyclin-dependent kinase (CDK) inhibitors p21 and p27 and to inhibit CDKs and induce hypophosphorylation of RB. GGTI treatment also decreases the levels of phospho-AKT and survivin, and this seems to mediate their ability to induce apoptosis.

  • Although in preclinical models FTIs are highly effective as antitumour agents, in clinical trials limited efficacy was observed. This is primarily due to poor patient selection. This in turn is due to our lack of understanding of the mechanism of action of FTIs. In the future, a major effort must be dedicated to identifying the prenylated proteins the inhibition of which is responsible for the antitumour effects of PTIs. This will be of great value not only for enhancing our understanding of the mechanism of action of FTIs and GGTIs, but also for selecting patients whose tumours are addicted to specific prenylated proteins and who are more likely to respond to these agents. Recent advances in techniques to characterize the human prenylome are likely to accelerate achieving these crucial goals in the prenylation field.

Abstract

Protein farnesylation and geranylgeranylation, together referred to as prenylation, are lipid post-translational modifications that are required for the transforming activity of many oncogenic proteins, including some RAS family members. This observation prompted the development of inhibitors of farnesyltransferase (FT) and geranylgeranyltransferase 1 (GGT1) as potential anticancer drugs. In this Review, we discuss the mechanisms by which FT and GGT1 inhibitors (FTIs and GGTIs, respectively) affect signal transduction pathways, cell cycle progression, proliferation and cell survival. In contrast to their preclinical efficacy, only a small subset of patients responds to FTIs. Identifying tumours that depend on farnesylation for survival remains a challenge, and strategies to overcome this are discussed. One GGTI has recently entered the clinic, and the safety and efficacy of GGTIs await results from clinical trials.

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Figure 1: RAS signalling pathways in mammalian cells.

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Acknowledgements

This work was partially supported by US National Institutes of Health grants CA067771 and CA098473 to S.M.S.

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Correspondence to Saïd M. Sebti.

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S.M.S. and A.D.H. are inventors of GGTI-2418.

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Supplementary information

Supplementary information S1 (table)

Compound structures and in vitro properties (PDF 573 kb)

Supplementary information S2 (table)

Effects of PTIs in intact cells (PDF 216 kb)

Supplementary information S3 (table)

Effects of PTIs in vivo (PDF 211 kb)

Supplementary information S4 (table)

Clinical trials with farnesyltransferase inhibitors (PDF 375 kb)

Supplementary information S5 (table)

Clinical trials with combinations including FTIs (PDF 229 kb)

Supplementary information S6 (figure)

Targeting KRAS-dependent tumours by exploiting synthetic lethality. (PDF 290 kb)

Glossary

Farnesylation

One of two types of prenylation. This involves the transfer of a farnesyl moiety to the cysteine of the C-terminal CaaX box of the target protein. Catalysed by farnesyltransferase.

Geranylgeranylation

This prenylation is catalysed by geranylgeranyltransferase 1 (GGT1) or GGT2. GGT1 transfers a geranylgeranyl moiety to the cysteine of the C-terminal CaaX box, and GGT2 acts on the cysteines of C-terminal CXC or CC motifs.

Prenylation

Also known as isoprenylation. An irreversible post-translational modification of proteins consisting of the covalent attachment of an isoprenyl lipid to a cysteine within four residues of the C terminus.

Myristoylated

A universal and irreversible co-translational modification of proteins involving the covalent attachment of a myristoyl group to an N-terminal amino acid of a nascent polypeptide. It is important for membrane targeting of the modified protein.

CaaX motif

This refers to the last four C-terminal amino acids that serve as a recognition motif for farnesyltransferase or geranylgeranyltransferase 1.C (cysteine) is the amino acid being modified, a is an aliphatic residue and X is any residue.

Intimal hyperplasia

The thickening of the innermost layer of a blood vessel as a complication of a reconstruction procedure or endarterectomy. It is the universal response of a vessel to injury and is an important reason for late bypass graft failure, particularly in vein and synthetic vascular grafts.

Neointima

A new or thickened layer of arterial intima (innermost layer of an artery or a vein) formed especially on a prosthesis or in atherosclerosis by migration and proliferation of cells from the media.

Palmitoylated

A post-translational modification, consisting of the covalent attachment of fatty acids to cysteine residues of membrane proteins, thought to further enhance membrane anchoring of previously prenylated proteins. In contrast to prenylation and myristoylation, it is reversible.

Prenylome

The subset of proteins in a cell or organism that is modified by prenylation.

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Berndt, N., Hamilton, A. & Sebti, S. Targeting protein prenylation for cancer therapy. Nat Rev Cancer 11, 775–791 (2011). https://doi.org/10.1038/nrc3151

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