Journal Article

Targeting protein prenylation for cancer therapy

Sebti, Saïd M., Berndt, Norbert, Hamilton, Andrew D.

2011

Overview

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. It was hoped that targeting protein prenylation would inhibit the oncogenic signalling of RAS family members. However, preclinical and clinical trials of prenyltransferase inhibitors have conflicting results. This Review discusses why these differences might occur and the future of targeting prenylation. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 1-Phosphatidylinositol 3-kinase / 631/154/436/108 / 631/45/173 / 631/67/1059/602 / 631/80/458/2133 / AKT protein / Alkyl and Aryl Transferases - antagonists & inhibitors / Angiogenesis / Animal models / Animals / Antimitotic agents / Antineoplastic agents / Antineoplastic Agents - therapeutic use / Antineoplastic drugs / Antitumor agents / Apoptosis / Biomedicine / Cancer / Cancer Research / Cancer therapies / Cell cycle / Cell Cycle - drug effects / Cell Proliferation - drug effects / Cell survival / Cell Survival - drug effects / Cellular signal transduction / Clinical trials / Cyclin-dependent kinase / Cyclin-dependent kinase inhibitor p27 / Cyclin-dependent kinases / Development and progression / Drug therapy / Enzyme Inhibitors - pharmacology / Enzyme Inhibitors - therapeutic use / Extracellular signal-regulated kinase / Farnesyl-diphosphate farnesyltransferase / Farnesyltransferase / Farnesyltranstransferase - antagonists & inhibitors / G1 phase / Genetic aspects / Geranylgeranyltransferase / Health aspects / Humans / K-Ras protein / Kinases / Life span / Lipids / Localization / Molecular Targeted Therapy / Monomeric GTP-Binding Proteins - metabolism / Neoplasms - drug therapy / Neuropeptides - metabolism / Patients / Post-translation / Protein Prenylation - drug effects / Proteins / Raf protein / Randomized Controlled Trials as Topic / Ras Homolog Enriched in Brain Protein / Regression analysis / review-article / Reviews / Signal transduction / Signal Transduction - drug effects / Therapeutic targets / Tumors