Abstract
ras is the oncogene most frequently found in human cancers, being detected in 30% of most human cancers and at significantly higher rates in certain cancers including pancreatic (90%) and colon (50%) [1]. Almost 10 years ago it was shown that a C-terminal lipid modification of Ras, catalyzed by a specific farnesyl-protein transferase (FPTase), was required for the function of both normal and oncogenic Ras proteins. This finding spurred the development of FPTase inhibitors (FTIs) as a potential cancer therapy directed at the ras oncogene. FTIs have exhibited potent antiproliferative activity in cell culture and animal tumor models with a surprising lack of toxicity to normal tissues. However, while FTIs were originally conceptualized as Ras-specific agents, their mechanism of action is significantly more complicated than originally envisioned.
Similar content being viewed by others
References
Barbacid M: ras Genes. Ann Rev Biochem 56: 779-827, 1987
Boguski MS, McCormick F: Proteins regulating Ras and its relatives. Nature 366: 643-654, 1993
Wittinghofer A, Nassar N: How Ras-related proteins talk to their effectors. Trends Bioch Sci 21: 488-491, 1996
Willumsen BM, Norris K, Papageorge AG, Hubbert NL, Lowy DR: Harvey murine sarcoma virus p21 ras protein: biological and biochemical significance of the cysteine nearest the carboxy terminus. EMBO J 3: 2581-2585, 1984
Casey PJ, Solski PA, Der CJ, Buss JE: p21 ras is modified by a farnesyl isoprenoid. Proc Natl Acad Sci USA 86: 8323-8327, 1989
Hancock JF, Magee AI, Childs JE, Marshall CJ: All ras proteins are polyisoprenylated but only some are palmitoylated. Cell 57: 1167-1177, 1989
Schafer WR, Kim R, Sterne R, Thorner J, Kim S-H, Rine J: Genetie and pharmacological suppression of oncogenic mutations in RAS genes of yeast and humans. Science 245: 379-385, 1989
Goldstein JL, Brown MS: Regulation of the mevalonate pathway. Nature (London) 343: 425-430, 1990
Zhang FL, Casey PJ: Protein prenylation: molecular mechanisms and functional consequences. Annu Rev Biochem 65: 241-269, 1996
Andres AD, Seabra MC, Brown MS, Armstrong SA, Smeland TE, Cremers FPM, Goldstein JL: eDNA cloning of component A of Rab geranylgeranyltransferase and demonstration of its role as a Rab escort protein. Cell 73: 1091-1099, 1993
Boyartchuk VL, Ashby MN, Rine J: Modulation of Ras and a-factor function by carboxyl-terminal proteolysis. Science 275: 1796-1800, 1997
Chen Y, Ma Y-T, Rando RR: Solubilization, partial purification, and affinity labeling of the membrane-bound isopreny-lated protein endoprotease. Biochemistry 35: 3227-3237, 1996
Hryeyna CA, Clarke S: Farnesyl cysteine C-terminal methyl-transferase activity is dependent upon the STE14 gene product in Saccharomyces cerevisiae. Mol Cell Biol 10: 5071-5076, 1990
Marr RS, Blair LC, Thorner J: Saccharomyces cerevisiae STE14 gene is required for COOH-terminal methylation of a-factor mating pheremone. J Biol Chem 265: 20057-20060, 1990
Hancock JF, Paterson H, Marshall CJ: A polybasic domain or palmitoylation is required in addition to the CAAX motif to localize p21ras to the plasma membrane. Cell 63: 133-139, 1990
Hancock JF, Cadwallader K, Marshall CJ: Methylation and proteolysis are essential for efficient membrane binding of prenylated p21K-ras(B). EMBO J 10: 641-646, 1991
Kato K, Cox AD, Hisaka MM, Graham SM, Buss JE, Der CJ: Isoprenoid addition to Ras protein is the critical modifieation for its membrane association and transforming activity. Proc Natl Acad Sci USA 89: 6403-6407, 1992
Goldstein JL, Brown MS, Stradley SJ, Reiss Y, Gierasch LM: Nonfarnesylated tetrapeptide inhibitors of protein farnesyltransferase. J Biol Chem 266: 15575-15578, 1991
Pompliano DL, Rands E, Schaber MD, Mosser SD, Anthony NJ, Gibbs JB: Steady-state kinetic mechanism of Ras farnesyl:protein transferase. Biochemistry 31: 3800-3807, 1992
Kohl NE, Wilson FR, Mosser SD, Giuliani E, DeSolms SJ, Conner MW, Anthony NJ, Holtz WJ, Gomez RP, Lee T-J, Smith RL, Graham SL, Hartman GD, Gibbs JB, Oliff A: Protein farnesyltransferase inhibitors block the growth of ras-dependent tumors in nude mice. Proc Natl Acad Sci USA 91: 9141-9145, 1994
Omer CA, Kohl NE: CAAX-competitive inhibitors of farnesyltransferase as anti-cancer agents. Trends in Pharmacological Sciences 18: 437-445, 1997
Nagasu T, Yoshimatsu K, Rowell C, Lewis MD, Garcia AM: Inhibition of human tumor xenograft growth by treatment with the farnesyl transferase inhibitor B956. Cancer Res 55: 5310-5314, 1995
Lerner EC, Qian Y, Blaskovich MA, Fossum RD, Vogt A, Sun J, Cox AD, Der CJ, Hamilton AD, Sebti SM. Ras CAAX peptidomimetic FTI-277 selectively blocks oncogenic Ras signaling by inducing cytoplasmic accumulation of inactive Ras-Raf complexes. J Biol Chem 270: 26802-26806, 1995
James GL, Goldstcin JL, Brown MS, Rawson TE, Somers TC, McDowell RS, Crowley CW, Lucas BK, Levinson AD, James C, Marsters J: Benzodiazepine peptidomimetics: potent inhibitors of Ras farnesylation in animal cells. Science 260: 1937-1942, 1993
Williams TM, Ciccarone TM, MacTough SC, Bock RL, Conner MW, Davide JP, Hamilton K, Koblan KS, Kohl NE, Kral AM, Mosser SD, Omer CA, Pompliano DL, Rands E, Schaber MD, Shah D, Wilson FR, Gibbs JB, Graham SL, Hartman GD, Oliff AI, Smith RL: 2-substituted piperazines as constrained amino acids. Application to the synthesis of potent, non carboxylic acid inhibitors of farnesyltransferase. J Med Chem 39: 1345-1348, 1996
Bishop WR, Bond R, Petrin J, Wang L, Patton R, Doll R, Njoroge C, Catino J, Schwartz J, Windsor W, Syto R, Schwartz J, Carr D, James L, Kirschmeier P: Novel tricyclic inhibitors of farnesyl protein transferase. J Biol Chem 270: 30611-30618, 1995
Mallams AK, Njoroge FG, Doll RJ, Snow ME, Kaminski JJ, Rossman RR, Vibulbhan B, Bishop WR, Kirschmeier P, Liu M, Bryant MS, Alvarez C, Carr D, James L, King I, Li Z, Lin C-C, Nardo C, Petrin J, Remiszewski SW, Taveras AG, Wang S, Wong J, Catino J, Girijavallabhan V, Ganguly AK: Antitumor 8-chlorobenzyocycloheptapyridines: a new class of selective, nonpeptidie, nonsulfhydryl inhibitors of ras farnesylation. Bioorg Med Chem 5: 93-99, 1997
Hara M, Akasaka K, Akinaga S, Okabe M, Nakano H, Gomez R, Wood D, Uh M, Tamanoi F: Identification of Ras farnesyltransferase inhibitors by microbial screening. Proc Natl Acad Sci USA 90: 2281-2285, 1993
Manne V, Yan N, Carboni JM, Tuomari AV, Ricca CS, Brown JG, Andahazy ML, Schmidt RJ, Patel D, Zahler R, Weinmann R, Der CJ, Cox AD, Hunt JT, Gordon EM, Barbacid M, Scizinger BR: Bisubstrate inhibitors of farnesyl-transferase: A novel class of specific inhibitors of ras transformed cells. Oncogene 10: 1763-1779, 1995
Prendergast GC, Davide JP, deSolms SJ, Giuliani EA, Graham SL, Gibbs JB, Oliff A, Kohl NE: Farnesyltransferase inhibition causes morphological reversion of ras-transformed cells by a complex mechanism that involves regu lation of the actin cytoskeleton. Mol Cell Biol 14: 4193-4202, 1994
Kohl NE, Omer CA, Conner MW, Anthony NJ, Davide JP, deSolms SJ, Giuliani EA, Gomez RP, Graham SL, Hamilton K, Handt LK, Hartman GD, Koblan KS, Kral AM, Miller PJ, Mosser SD, O'Neill TJ, Rands E, Schaber MD, Gibbs JB, Oliff A: Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice. Nature Med 1: 792-797, 1995
Sepp-Lorenzino L, Ma Z, Rands F, Kohl NE, Gibbs JR, Oliff A, Rosen N: A peptidomimetic inhibitor of larnesyl: protein transferase blocks the anchorage-dependent and-independent growth of human tumor cell lines. Cancer Res 55: 5302-5309, 1995
Sun J, Qian Y, Hamilton AD, Sebti SM: Ras CAAX peptidomimetic FTI 276 selectively blocks tumor growth in nude mice of a human lung carcinoma with K-Ras mutation and p53 deletion. Cancer Res 55: 4243-4247, 1995
Whyte DB, Kirschmeier P, Hockenberry TN, Nunez-Oliva I, James L, Catino JJ, Bishop WR, Pai J-K: K-and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors. J Biol Chem 272: 14459-14464, 1997
Rowell CA, Kowalczyk JJ, Lewis MD, Garcia AM: Direct demonstration of geranylgeranylation and farnesylation of Ki-Ras in vivo. J Biol Chem 272: 14093-14097, 1997
James GL, Goldstein JL, Brown MS: Polylysine and CVIM sequences of K-RasB dictate specificity of prenylation and confer resistance to benzodiazepine peptidomimetic in vitro. J Biol Chem 270: 6221-6226, 1995
Zhang FL, Kirschmeier P, Carr D, James L, Bond RW, Wang L, Patton R, Windsor WT, Syto R, Zhang R, Bishop WR: Characterization of Ha-Ras, N-Ras, Ki-Ras4a, and Ki-Ras4B as in vitro substrates for farnesyl protein transferase and geranylgeranyl protein transferase type I. J Biol Chem 272: 10232-10239, 1997
Hancock JF, Cadwallader K, Paterson H, Marshall CJ: A CAAX or a CAAL motif and a second signal are sufficient for plasma membrane targeting of Ras proteins. EMBO J 10: 4033-4039, 1991
Adamson P, Marshall CJ, Hall A, Tilbrook PA: Post-translational modifications of p21rho proteins. J Biol Chem 267: 20033-20038, 1992
Lebowitz PF, Casey PJ, Prendergast GC, Thissen JA: Farnesyltransferase inhibitors alter the prenylation and growthstimulating function of RhobB. J Biol Chem 272: 15591-15594, 1997
Clark GJ, Kinch MS, Rogers-Graham K, Sebti SM, Hamilton AD, Der CJ: The Ras-related protein Rheb is farnesylated and antagonizes Ras signaling and transformation. J Biol Chem 272: 10608-10615, 1997
Diamond RH, Cressman DE, Laz TM, Abrams CS, Taub R: PRL-1, a unique nuclear protein tyrosine phosphatase, affects cell growth. Mol Cell Biol 14: 3752-3762, 1994
Cates CA, Michael RL, Stayrook KR, Harvey KA, Burke YD, Randall SK, Crowell PL, Crowell DN: Prenylation of oncogenic human PTP-CAAX protein tyrosine phosphatases. Cancer Lett 110: 49-55, 1996
Yaglom JA, Goldberg AL, Finley D, Sherman MY: The molecular chaperone Ydj1 is required for the p34CDC28-dependent phosphorylation of the cyclin Cln3 that signals its degradation. Mol Cell Biol 16: 3679-3684, 1996
Kanazawa M, Terada K, Kato S, Mori M: HSDJ, a human homolog of DnaJ, is farnesylated and is involved in protein import into mitochondria. J Biochem 121: 890-895, 1997
Gotte K, Girzalsky W, Linkert M, Baumgart E, Kammerer S, Kunau W-H, Erdmann R: Pex19p, a tarnesylated protein essential for peroxisome biogenesis. Mol Cell Biol 18: 616-628, 1998
James GL, Brown MS, Cobb MH, Goldstein JL: Benzodiazepine peptidomimetic BZA-5B interrupts the MAP kinase activation pathway in H-Ras-transformed Rat-1 cells, but not in untransformed cells. J Biol Chem 269: 27705-27714, 1994
Lebowitz PF, Sakamuro D, Prendergast GC: Farnesyl transferase inhibitors induce apoptosis of Ras transformed cells denied substratum attachment. Cancer Res 57: 708-713, 1997
Barrington RE, Subler MA, Rands E, Omer CA, Miller PJ, Hundley JE, Koester SK, Troyer DA, Bearss DJ, Conner MW, Gibbs JB, Hamilton K, Koblan KS, Mosser SD, O'Neill TJ, Schaber MD, Senderak ET, Windle JJ, Oliff A, Kohl NE: A farnesyltransferase inhibitor induces tumor regression in transgenic mice harboring multiple oncogenic mutations by mediating alterations in both cell cycle control and apoptosis. Mol Cell Biol 18: 85-92, 1998
Prendergast GC, Davide JP, Lebowitz PF, Wechsler-Reya R, Kohl NE: Resistance of a variant ras-transformed cell line to phenotypic reversion by farnesyl transferase inhibitors. Cancer Res 56: 2626-2632, 1996
Bernhard EJ, Kao G, Cox AD, Sebti SM, Hamilton AD, Muschel RJ, McKenna WG: The farnesyltransferase inhibitor FTI-277 radiosensitizes H-ras-transformed rat embryo fibroblasts. Cancer Res 56: 1727-1730, 1996
Bernhard EJ, McKenny WG, Hamilton AD, Sebti SM, Qian Y, Wu JM, Muschel RJ: Inhibiting Ras prenylation increases the radiosensitivity of human tumor cell lines with activating mutations of ras oncogenes. Cancer Res 58: 1754-1761, 1998
Moasser MM, Sepp-Lorenzino L, Kohl NE, Oliff A, Balog A, Su D-S, Danishefsky SJ, Rosen N: Farnesyl transferase inhibitors cause enhanced mitotic sensitivity to taxol and epothilones. Proc Natl Acad Sci USA 95: 1369-1374, 1998
Fokstuen T, Bendix-Rabo Y, Zhou J N, Karlson J, Platz A, Shoshan MC, Hansson J, Linder S: The ras farnesylation inhibitor BZA-5B increases the resistance to cisplatin in a human melanoma cell line. Anticancer Res 17: 2347-2352, 1997
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Lobell, R.B., Kohl, N.E. Pre-clinical development of farnesyltransferase inhibitors. Cancer Metastasis Rev 17, 203–210 (1998). https://doi.org/10.1023/A:1006018922878
Issue Date:
DOI: https://doi.org/10.1023/A:1006018922878