Cited by 622Protein Kinase Regulation and GTPase SignalingCancer, Lipids, and MetabolismProtein Tyrosine Phosphatases

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Targeting protein prenylation for cancer therapy

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Berndt, Norbert, Hamilton, Andrew D., Sebti, Saïd M.·2011·Nature Reviews Cancer

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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 geranylgeranyl-transferase 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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Brain G protein gamma subunits contain an all-trans-geranylgeranylcysteine methyl ester at their carboxyl termini.
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G protein gamma subunits contain a 20-carbon isoprenoid.
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Ras CAAX peptidomimetic FTI 276 selectively blocks tumor growth in nude mice of a human lung carcinoma with K-Ras mutation and p53 deletion.
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Akt Protein Kinase Inhibits Rac1-GTP Binding through Phosphorylation at Serine 71 of Rac1
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“Phosphorylation of CDC42, RHOB and RHEB inhibits their functio”
Peptidomimetic inhibitors of Ras farnesylation and function in whole cells.
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Identification of Geranylgeranyl-Modified Proteins in HeLa Cells
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Thematic Review Series: Lipid Posttranslational Modifications. Prelamin A, Zmpste24, misshapen cell nuclei, and progeria—new evidence suggesting that protein farnesylation could be important for disease pathogenesis
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Farnesyltransferase Inhibitors Alter the Prenylation and Growth-stimulating Function of RhoB
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“Although RHOB was shown to be farnesylated in vitro by FT, and the treatment of cultured cells with the FTI L-739749 increases the levels of RHOB-G”
DBC2 , a candidate for a tumor suppressor gene involved in breast cancer
Hamaguchi, M., Meth, J. L., von Klitzing, C., Wei, W., Esposito, D., Rodgers, L., Walsh, T., Welcsh, P. L., King, M., & Wigler, M. H. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.212516099 · Cited by 211 · cited 1×
“, deleted in breast cancer 2 (DBC2; also known as RHOBTB2”
Inhibiting farnesylation reverses the nuclear morphology defect in a HeLa cell model for Hutchinson-Gilford progeria syndrome
Mallampalli, M. P., Huyer, G., Bendale, P. M., Gelb, M. H., & Michaelis, S. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0503712102 · Cited by 210
Farnesyl transferase inhibitors cause enhanced mitotic sensitivity to taxol and epothilones
Moasser, M. M., Sepp‐Lorenzino, L., Kohl, N. E., Oliff, A. I., Balog, A., Su, D., Danishefsky, S. J., & Rosen, N. X. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.4.1369 · Cited by 210 · cited 1×
“AML II 145 (74) 22 CR, 3 PR, 50 SD and 58 PD and MD HDJ2 ↓ 17.”
Antitumor efficacy of a novel class of non-thiol-containing peptidomimetic inhibitors of farnesyltransferase and geranylgeranyltransferase I: combination therapy with the cytotoxic agents cisplatin, Taxol, and gemcitabine.
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The Tumor Suppressor PP2A Aβ Regulates the RalA GTPase
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Both Farnesylated and Geranylgeranylated RhoB Inhibit Malignant Transformation and Suppress Human Tumor Growth in Nude Mice
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“More importantly, in human cancer cells of epithelial origin, both RHOB-F and RHOB-GG have tumour suppressive activity, further arguing against the inhibition of RHOB farnesylation playing a part in FTI antitumour activit”
Self-citation
The CaaX motif is required for isoprenylation, carboxyl methylation, and nuclear membrane association of lamin B2.
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In vivo antiviral efficacy of prenylation inhibitors against hepatitis delta virus
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The Geranylgeranyltransferase-I Inhibitor GGTI-298 Arrests Human Tumor Cells in G0/G1 and Induces p21WAF1/CIP1/SDI1 in a p53-independent Manner
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Inactivation of Icmt inhibits transformation by oncogenic K-Ras and B-Raf
Bergö, M. O., Gavino, B. J., Hong, C., Beigneux, A. P., McMahon, M., Casey, P. J., & Young, S. G. (2004) · Journal of Clinical Investigation · doi:10.1172/jci18829 · Cited by 185 · cited 1×
“Second, the carboxyl group in the now C-terminal prenylated cysteine is methylated by isoprenylcysteine carboxyl methyltransferase (ICMT”
Loss of RhoB Expression in Human Lung Cancer Progression
Mazières, J., Antonia, T., Daste, G., Muro‐Cacho, C., Berchery, D., Tillement, V., Pradines, A., Sebti, S. M., & Favre, G. (2004) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-03-0149 · Cited by 183 · cited 1×
“Consistent with RHOB functioning as a tumour suppressor, RHOB is downregulated in several human cancer”
Self-citation
Farnesyl transferase inhibitors induce apoptosis of Ras-transformed cells denied substratum attachment.
Lebowitz, P. F., Sakamuro, D., & Prendergast, G. C. (1997) · PubMed · Cited by 183
Inactivation of Icmt inhibits transformation by oncogenic K-Ras and B-Raf
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Protein Farnesyltransferase Inhibitors Exhibit Potent Antimalarial Activity
Nallan, L., Bauer, K. D., Bendale, P. M., Rivas, K. L., Yokoyama, K., Horney, C. P., Pendyala, P. R., FLOYD, D. M., Lombardo, L. J., Williams, D. K., et al. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm0491039 · Cited by 178
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Specific Isoprenoid Modification Is Required for Function of Normal, but Not Oncogenic, Ras Protein
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Phosphorylation states of Cdc42 and RhoA regulate their interactions with Rho GDP dissociation inhibitor and their extraction from biological membranes
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“For example, protein kinase C (PKC)- or PKA-mediated phosphorylation of CDC42, KRAS, RAP1A and RHOA induces their removal from the cell membran”
Analysis of the eukaryotic prenylome by isoprenoid affinity tagging
Nguyen, U. T. T., Guo, Z., Delon, C., Wu, Y., Deraeve, C., Fränzel, B., Bon, R. S., Blankenfeldt, W., Goody, R. S., Waldmann, H., et al. (2009) · Nature Chemical Biology · doi:10.1038/nchembio.149 · Cited by 176
RERG Is a Novel ras-related, Estrogen-regulated and Growth-inhibitory Gene in Breast Cancer
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Protein farnesylation: Implications for normal physiology, malignant transformation, and cancer therapy
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“Contemporary reviews have estimated that several hundred proteins are subject to prenylatio”
Self-citation
A Farnesyltransferase Inhibitor Induces Tumor Regression in Transgenic Mice Harboring Multiple Oncogenic Mutations by Mediating Alterations in Both Cell Cycle Control and Apoptosis
Barrington, R. E., Subler, M. A., Rands, E., Omer, C. A., Miller, P. J., Hundley, J. E., Koester, S. K., Troyer, D. A., Bearss, D. J., Conner, M. W., et al. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.1.85 · Cited by 169 · cited 5×
“Small-cell lung cancer II 20 (62) 1 SD ND 0 No objective response.”
Influential
Requirement for Rac1 in a K-ras–Induced Lung Cancer in the Mouse
Kissil, J. L., Walmsley, M. J., Hanlon, L., Haigis, K. M., Kim, C. F. B., Sweet-Cordero, A., Eckman, M. S., Tuveson, D. A., Capobianco, A. J., Tybulewicz, V. L. J., et al. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-2300 · Cited by 167 · cited 1×
“Furthermore, RAC1 is required to induce KRAS-driven lung cancer in mic”
CAAX Geranylgeranyl Transferase Transfers Farnesyl as Efficiently as Geranylgeranyl to RhoB
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“, the laboratory of Goldstein and Brown has shown using purified components that RHOB is farnesylated by GGT1 but not by F”
Prenylated Proteins: the Structure of the Isoprenoid Group
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Towards Complete Sets of Farnesylated and Geranylgeranylated Proteins
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“Future directions and challenges Despite the conceptual advances that have been made over the past decade, in our opinion, the major challenge in this field is the following question: which PT substrates are crucial for the proliferation or survival of different cancer types? Or, in other words, does the antitumour ac…”
The Farnesyl Transferase Inhibitor (FTI) SCH66336 (lonafarnib) Inhibits Rheb Farnesylation and mTOR Signaling
Basso, A. D., Mirza, A., Liu, G., Long, B. J., Bishop, W. R., & Kirschmeier, P. T. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m503763200 · Cited by 162
RhoE function is regulated by ROCK I‐mediated phosphorylation
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RhoB Alteration Is Necessary for Apoptotic and Antineoplastic Responses to Farnesyltransferase Inhibitors
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“Taken together, these results suggest that increased RHOB protein levels, not inhibition of RHOB farnesylation, may contribute to some of the effects of FTI”
Farnesylation of Cenp-F is required for G2/M progression and degradation after mitosis
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The farnesyltransferase inhibitor FTI-277 radiosensitizes H-ras-transformed rat embryo fibroblasts.
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Geranylgeranylated RhoB mediates suppression of human tumor cell growth by farnesyltransferase inhibitors.
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RB and cyclin dependent kinase pathways: defining a distinction between RB and p16 loss in lung cancer
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Structure of rhodotorucine A, a novel lipopeptide, inducing mating tube formation in Rhodosporidiumtoruloides
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DrosophilaRheb GTPase is required for cell cycle progression and cell growth
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A randomized phase 3 study of tipifarnib compared with best supportive care, including hydroxyurea, in the treatment of newly diagnosed acute myeloid leukemia in patients 70 years or older
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Evidence for a Catalytic Role of Zinc in Protein Farnesyltransferase
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Antitumor effect of a farnesyl protein transferase inhibitor in mammary and lymphoid tumors overexpressing N-ras in transgenic mice.
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Inactivation of Rheb by PRAK-mediated phosphorylation is essential for energy-depletion-induced suppression of mTORC1
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Absence of the CAAX Endoprotease Rce1: Effects on Cell Growth and Transformation
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Phosphorylation states of Cdc42 and RhoA regulate their interactions with Rho GDP dissociation inhibitor and their extraction from biological membranes
Forget, M.-A., Desrosiers, R. R., Gingras, D. J., et al. (2002) · Biochemical Journal · doi:10.1042/bj3610243 · Cited by 140
Chemical genetics identifies Rab geranylgeranyl transferase as an apoptotic target of farnesyl transferase inhibitors
Lackner, M. R., Kindt, R. M., Carroll, P. M., Brown, K. A., Cancilla, M. R., Chen, C., de Silva, H., Franke, Y., Guan, B., Heuer, T., et al. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.03.024 · Cited by 133 · cited 1×
“MDS I 61 (68) 3 CR and 13 PR FT ↓ by 75% 26.”
A 2-gene classifier for predicting response to the farnesyltransferase inhibitor tipifarnib in acute myeloid leukemia
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“gov/drugdictionary?CdrID=42626">tipifarnib (also known as R115777”
The Farnesyltransferase Inhibitor, FTI-2153, Blocks Bipolar Spindle Formation and Chromosome Alignment and Causes Prometaphase Accumulation during Mitosis of Human Lung Cancer Cells
Crespo, N. C., Ohkanda, J., Yen, T. J., Hamilton, A. D., & Sebti, S. M. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m006213200 · Cited by 127 · cited 3×
“Advanced solid tumours I 22 (54) 1 CR and 1 PR FT ↓ 12.”
InfluentialSelf-citation
Aurora-A Phosphorylates, Activates, and Relocalizes the Small GTPase RalA
Lim, K.-H., Brady, D. C., Kashatus, D. F., Ancrile, B. B., Der, C. J., Cox, A. D., & Counter, C. M. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.00916-08 · Cited by 126
The p21 RAS Farnesyltransferase α Subunit in TGF-β and Activin Signaling
Wang, T., Danielson, P. D., Li, B.-Y., Shah, P. C., Kim, S. D., & Donahoe, P. K. (1996) · Science · doi:10.1126/science.271.5252.1120 · Cited by 125
Farnesyltransferase inhibitor R115777 in myelodysplastic syndrome: clinical and biologic activities in the phase 1 setting
Kurzrock, R., Kantarjian, H. M., Cortes, J. E., Singhania, N., Thomas, D. A., Wilson, E. F., Wright, J. J., Freireich, E. J., Talpaz, M., & Sebti, S. M. (2003) · Blood · doi:10.1182/blood-2002-11-3359 · Cited by 125
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The Tyrosine Phosphatase PRL-1 Localizes to the Endoplasmic Reticulum and the Mitotic Spindle and Is Required for Normal Mitosis
Wang, J., Kirby, C., & Herbst, R. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m206407200 · Cited by 123 · cited 5×
“Advanced solid tumours I 31 (58) 8 PR and 12 SD ND 25.”
Influential
Preclinical and clinical pharmacodynamic assessment of L-778,123, a dual inhibitor of farnesyl:protein transferase and geranylgeranyl:protein transferase type-I.
Lobell, R. B., Liu, D., Buser, C. A., Davide, J. P., DePuy, E., Hamilton, K., Koblan, K. S., Lee, Y., Mosser, S. D., Motzel, S. L., et al. (2002) · PubMed · Cited by 121
A Farnesyl-Protein Transferase Inhibitor Induces p21 Expression and G1 Block in p53 Wild Type Tumor Cells
Sepp‐Lorenzino, L., & Rosen, N. X. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.32.20243 · Cited by 117 · cited 4×
“Advanced pancreatic cancer I 10 (59) 1 PR, 5 SD, and 4 PD and MD HDJ2 ↓ 10.”
Influential
Inhibition of Rho GTPases with Protein Prenyltransferase Inhibitors Prevents Leukocyte Recruitment to the Central Nervous System and Attenuates Clinical Signs of Disease in an Animal Model of Multiple Sclerosis
Walters, C. E., Pryce, G., Hankey, D. J. R., Sebti, S. M., Hamilton, A. D., Baker, D., Greenwood, J., & Adamson, P. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.168.8.4087 · Cited by 115
Self-citation
Platelet-derived Growth Factor Receptor Tyrosine Phosphorylation Requires Protein Geranylgeranylation but not Farnesylation
McGuire, T. F., Qian, Y., Vogt, A., Hamilton, A. D., & Sebti, S. M. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.44.27402 · Cited by 115 · cited 1×
“In addition, GGTIs inhibit platelet-derived growth factor (PDGF)-stimulation of PDGF receptor (PDGFR)-mediated tyrosine phosphorylation and MAPK signalling, suggesting that PDGFR phosphorylation is mediated by a GGT1 substrat”
Self-citation
GGTase-I deficiency reduces tumor formation and improves survival in mice with K-RAS–induced lung cancer
Sjogren, A.-K. M., Andersson, K., Liu, M., Cutts, B. A., Karlsson, C., Wahlstrom, A. M., Dalin, M. G., Weinbaum, C., Casey, P. J., Tarkowski, A., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30868 · Cited by 115
Potent inhibition of human tumor p21ras farnesyltransferase by A1A2-lacking p21ras CA1A2X peptidomimetics.
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Thematic review series: Lipid Posttranslational Modifications. Fighting parasitic disease by blocking protein farnesylation
Eastman, R. T., C, F. S. B. A., Yokoyama, K., Gelb, M. H., & A, W. C. V. V. (2005) · Journal of Lipid Research · doi:10.1194/jlr.r500016-jlr200 · Cited by 114
Targeting the protein prenyltransferases efficiently reduces tumor development in mice with K-RAS-induced lung cancer
Liu, M., Sjogren, A.-K. M., Karlsson, C., Ibrahim, M. X., Andersson, K., Olofsson, F. J., Wahlstrom, A. M., Dalin, M. G., Yu, H., Chen, Z., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0908396107 · Cited by 113 · cited 1×
“Two other recent studies by Bergo and colleagues have shown that conditional Fntb deficienc”
The farnesyl protein transferase inhibitor SCH66336 synergizes with taxanes in vitro and enhances their antitumor activity in vivo
Shi, B., Yaremko, B., Hajian, G., Terracina, G., Bishop, W. R., Liu, M., & Nielsen, L. L. (2000) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s002800000170 · Cited by 113
Protein Farnesyltransferase Inhibitor (SCH 66336) Abolishes NF-κB Activation Induced by Various Carcinogens and Inflammatory Stimuli Leading to Suppression of NF-κB-regulated Gene Expression and Up-regulation of Apoptosis
Takada, Y., Khuri, F. R., & Aggarwal, B. B. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m400963200 · Cited by 113
Suppression of rho B expression in invasive carcinoma from head and neck cancer patients.
Adnane, J., Muro‐Cacho, C., Mathews, L., Sebti, S. M., & Muñoz-Antonia, T. (2002) · PubMed · Cited by 113
Self-citation
Tumorigenic activity and therapeutic inhibition of Rheb GTPasePreprint
Mavrakis, K. J., Zhu, H., Silva, R. L. A., Mills, J. R., Teruya‐Feldstein, J., Lowe, S. W., Tam, W., Pelletier, J., & Wendel, H. (2008) · Genes & Development · doi:10.1101/gad.1690808 · Cited by 113 · cited 1×
“Similarly, RHEB is overexpressed in some lymphomas, which have increased mTOR activity and enhanced sensitivity to FTI”
Yeast CAL1 is a structural and functional homologue to the DPR1 (RAM) gene involved in ras processing
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The Synergistic Combination of the Farnesyl Transferase Inhibitor Lonafarnib and Paclitaxel Enhances Tubulin Acetylation and Requires a Functional Tubulin Deacetylase
Marcus, A. I., Zhou, J., O’Brate, A., Hamel, E., Wong, J. Y. Y., Nivens, M. C., El‐Naggar, A. K., Yao, T., Khuri, F. R., & Giannakakou, P. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-3757 · Cited by 109 · cited 1×
“First, they showed that lonafarnib in combination with paclitaxel enhances tubulin acetylation more than the effect of either drug alone, and that this is due to the inhibition of histone deacetylase 6 (HDAC6”
Farnesyltransferase inhibitors induce cytochrome c release and caspase 3 activation preferentially in transformed cells
Suzuki, N., Urano, J., & Tamanoi, F. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.26.15356 · Cited by 108 · cited 3×
“Metastatic colon cancer II 21 (64) 3 SD ND 0 No objective response”
Influential
Identification of Dominant Negative Mutants of Rheb GTPase and Their Use to Implicate the Involvement of Human Rheb in the Activation of p70S6K
Tabancay, A. P., Gau, C., Machado, I. M. P., Uhlmann, E. J., Gutmann, D. H., Guo, L., & Tamanoi, F. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m306553200 · Cited by 107
Mouse mammary tumor virus-Ki-rasB transgenic mice develop mammary carcinomas that can be growth-inhibited by a farnesyl:protein transferase inhibitor.
Omer, C. A., Chen, Z., Diehl, R. E., Conner, M. W., Chen, H. Y., Trumbauer, M. E., Gopal-Truter, S., Seeburger, G., Bhimnathwala, H., Abrams, M. T., et al. (2000) · PubMed · Cited by 105
Cdk inhibitors, roscovitine and olomoucine, synergize with farnesyltransferase inhibitor (FTI) to induce efficient apoptosis of human cancer cell lines
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Berndt, N. & Sebti, S. M. Measuring protein farnesylation and geranylgeranylation and using prenyltransferase inhibitors as chemical probes and anticancer agents. Nature Protoc. (in the press).

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Authors: Berndt, N., Hamilton, A. D., & Sebti, S. M.
Affiliations: Moffitt Cancer Center (US)
University of Oxford (GB)
ORCID: Hamilton, Andrew D.
Venue: Nature Reviews Cancer
Publisher: Springer Science and Business Media LLC
Published: 2011-10-24
Volume: 11
Issue: 11
Pages: 775-791
ISSN: 1474-175X (ISSN-L)
1474-1768
DOI: 10.1038/nrc3151
PMC: PMC4037130
OpenAlex: W2002252224
Cited by: 614
References: 221
Citations by year: 2026: 25 · 2025: 24 · 2024: 20 · 2023: 42 · 2022: 34 · 2021: 52 · 2020: 59 · 2019: 46 · 2018: 42 · 2017: 46 · 2016: 52 · 2015: 47 · 2014: 48 · 2013: 44 · 2012: 30
FWCI: 3.60
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature reviews. Cancer (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health
National Cancer Institute (CA098473, U19CA067771, CA067771, R01CA098473)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Keywords: protein prenylation, farnesylation, geranylgeranylation, farnesyltransferase inhibitors, signal transduction, cell cycle progression, tumor cell survival, anticancer drug development, clinical trial results
MeSH terms: Ras Homolog Enriched in Brain Protein, Animals, Antineoplastic Agents, Cell Cycle, Cell Survival, Enzyme Inhibitors, Humans, Neoplasms, Neuropeptides, Signal Transduction, Randomized Controlled Trials as Topic, Protein Prenylation, Alkyl and Aryl Transferases, Monomeric GTP-Binding Proteins, Cell Proliferation, Farnesyltranstransferase, Molecular Targeted Therapy

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Targeting protein prenylation for cancer therapy

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