Cancer Letters
Volume 206, Issue 2 , Pages 159-167 , 8 April 2004

Perspectives on farnesyl transferase inhibitors in cancer therapy

Received 29 July 2003 ,Accepted 5 August 2003.

References 

  1. Zhang FL, Casey PJ. Protein prenylation: molecular mechanisms and functional consequences. Annu. Rev. Biochem. 1996;65:241–269
  2. Casey PJ. Biochemistry of protein prenylation. J. Lipid Res. 1992;33:1731–1740
  3. Casey PJ, Seabra MC. Protein prenyltransferases. J. Biol. Chem. 1996;271:5289–5292
  4. Whyte DB, Kirschmeier P, Hockenberry TN, NunezOliva I, James L, Catino JJ, et al.  K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors. J. Biol. Chem. 1997;272:14459–14464
  5. Baron R, Fourcade E, Lajoie-Mazenc I, Allal C, Couderc B, Barbaras R, et al.  RhoB prenylation is driven by the three carboxyl-terminal amino acids of the protein: evidenced in vivo by an anti-farnesyl cysteine antibody. Proc. Natl. Acad. Sci. USA. 2000;97:11626–11631
  6. Lebowitz PF, Casey PJ, Prendergast GC, Thissen JA. Farnesyltransferase inhibitors alter the prenylation and growth-stimulating function of RhoB. J. Biol. Chem. 1997;272:15591–15594
  7. Sebti SM, Hamilton AD. Farnesyltransferase and geranylgeranyltransferase I inhibitors in cancer therapy: important mechanistic and bench to bedside issues. Expert Opin. Investig. Drugs. 2000;9:2767–2782
  8. James GL, Goldstein JL, Brown MS, Rawson TE, Somers TC, Mcdowell RS, et al.  Benzodiazepine peptidomimetics—potent inhibitors of Ras farnesylation in animal cells. Science. 1993;260:1937–1942
  9. Kohl NE, Mosser SD, Desolms SJ, Giuliani EA, Pompliano DL, Graham SL, et al.  Selective inhibition of Ras-dependent transformation by a farnesyltransferase inhibitor. Science. 1993;260:1934–1937
  10. Manne V, Ricca CS, Brown JG, Tuomari AV, Yan N, Patel D, et al.  Ras farnesylation as a target for novel antitumor agents: potent and selective farnesyl diphosphate analog inhibitors of farnesyltransferase. Drug Develop. Res. 1995;34:121–137
  11. Cox AD, Garcia AM, Westwick JK, Kowalczyk JJ, Lewis MD, Brenner DA, et al. The CAAX peptidomimetic compound B581 specifically blocks farnesylated, but not geranylgeranylated or myristylated, oncogenic ras signaling and transformation. J. Biol. Chem. 1994;269:19203–19206
  12. 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. 1994;269:27705–27714
  13. Sepp-Lorenzino L, Ma ZP, Bands E, Kohl NE, Gibbs JB, Oliff A, et al. Peptidomimetic inhibitor of farnesyl:protein transferase blocks the anchorage-dependent and -independent growth of human tumor cell lines. Cancer Res. 1995;55:5302–5309
  14. Lerner EC, Qian YM, Blaskovich MA, Fossum RD, Vogt A, Sun JZ, et al.  Ras CAAX peptidomimetic FTI-277 selectively blocks oncogenic ras signaling by inducing cytoplasmic accumulation of inactive Ras–Raf complexes. J. Biol. Chem. 1995;270:26802–26806
  15. Jiang K, Coppola D, Crespo NC, Nicosia SV, Hamilton AD, Sebti SM, et al. The phosphoinositide 3-OH kinase/AKT2 pathway as a critical target for farnesyltransferase inhibitor-induced apoptosis. Mol. Cell. Biol. 2000;20:139–148
  16. 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. 1995;55:5310–5314
  17. Law BK, Norgaard P, Gnudi L, Kahn BB, Poulson HS, Moses HL. Inhibition of DNA synthesis by a farnesyltransferase inhibitor involves inhibition of the p70(s6k) pathway. J. Biol. Chem. 1999;274:4743–4748
  18. Miquel K, Pradines A, Sun J, Qian Y, Hamilton AD, Sebti SA, et al. GGTI-298 induces G0/G1 block and apoptosis whereas FTI-277 causes G2/M enrichment in A549 cells. Cancer Res. 1997;57:1846–1850
  19. Vogt A, Sun JZ, Qian YM, Hamilton AD, Sebti SM. The geranylgeranyltransferase-I inhibitor GGTI-298 arrests human tumor cells in G(0)/G(1) and induces p21(WAF1/CIP1/SDI1) in a p53-independent manner. J. Biol. Chem. 1997;272:27224–27229
  20. Ashar HR, James L, Gray K, Carr D, McGuirk M, Maxwell E, et al.  The farnesyl transferase inhibitor SCH 66336 induces a G(2)→M or G(1) pause in sensitive human tumor cell lines. Exp. Cell Res. 2001;262:17–27
  21. Tamanoi F, Gau CL, Jiang C, Edamatsu H, Kato-Stankiewicz J. Protein farnesylation in mammalian cells: effects of farnesyltransferase inhibitors on cancer cells. Cell. Mol. Life Sci. 2001;58:1636–1649
  22. Sepp-Lorenzino L, Rosen N. A farnesyl-protein transferase inhibitor induces p21 expression and G(1) block in p53 wild type tumor cells. J. Biol. Chem. 1998;273:20243–20251
  23. Mazzocca A, Giusti S, Hamilton AD, Sebti SM, Pantaleo P, Carloni V. Growth inhibition by the farnesyltransferase inhibitor FTI-277 involves Bcl-2 expression and defective association with Raf-1 in liver cancer cell lines. Mol. Pharmacol. 2003;63:159–166
  24. Crespo NC, Ohkanda J, Yen TJ, Hamilton AD, Sebti SM. The farnesyltransferase inhibitor, FTI-2153, blocks bipolar spindle formation and chromosome alignment and causes prometaphase accumulation during mitosis of human lung cancer cells. J. Biol. Chem. 2001;276:16161–16167
  25. Crespo NC, Delarue F, Ohkanda J, Carrico D, Hamilton AD, Sebti SM. The farnesyltransferase inhibitor, FTI-2153, inhibits bipolar spindle formation during mitosis independently of transformation and Ras and p53 mutation status. Cell Death Differ. 2002;9:702–709
  26. Suzuki N, Urano J, Tamanoi F. Farnesyltransferase inhibitors induce cytochrome c release and caspase 3 activation preferentially in transformed cells. Proc. Natl. Acad. Sci. USA. 1998;95:15356–15361
  27. Rose WC, Lee FY, Fairchild CR, Lynch M, Monticello T, Kramer RA, et al. Preclinical antitumor activity of BMS-214662, a highly apoptotic and novel farnesyltransferase inhibitor. Cancer Res. 2001;61:7507–7517
  28. Lebowitz PF, Sakamuro D, Prendergast GC. Farnesyl transferase inhibitors induce apoptosis of Ras-transformed cells denied substratum attachment. Cancer Res. 1997;57:708–713
  29. Brassard DL, English JM, Malkowski M, Kirschmeier P, Nagabhushan TL, Bishop WR. Inhibitors of farnesyl protein transferase and MEK1,2 induce apoptosis in fibroblasts transformed with farnesylated but not geranylgeranylated H-Ras. Exp. Cell Res. 2002;273:138–146
  30. Liu M, Bryant MS, Chen J, Lee S, Yaremko B, Lipari P, et al.  Antitumor activity of SCH 66336, an orally bioavailable tricyclic inhibitor of farnesyl protein transferase, in human tumor xenograft models and wap–ras transgenic mice. Cancer Res. 1998;58:4947–4956
  31. Barrington RE, Subler MA, Rands E, Omer CA, Miller PJ, Hundley JE, et al.  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. 1998;18:85–92
  32. Sun JZ, Qian YM, 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. 1995;55:4243–4247
  33. Lantry LE, Zhang Z, Yao R, Crist KA, Wang Y, Ohkanda J, et al.  Effect of farnesyltransferase inhibitor FTI-276 on established lung adenomas from A/J mice induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Carcinogenesis. 2000;21:113–116
  34. Kohl NE, Omer CA, Conner MW, Anthony NJ, Davide JP, Desolms SJ, et al.  Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice. Nat. Med. 1995;1:792–797
  35. Lerner EA, Zhang T-T, Knowles DB, Qian Y, Hamilton AD, Sebti SM. 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 inhibitors in human tumor cell lines. Oncogene. 1997;15:1283–1288
  36. Prendergast GC, Davide JP, Desolms SJ, Giuliani EA, Graham SL, Gibbs JB, et al.  Farnesyltransferase inhibition causes morphological reversion of ras-transformed cells by a complex mechanism that involves regulation of the actin cytoskeleton. Mol. Cell. Biol. 1994;14:4193–4202
  37. Lebowitz PF, Davide JP, Prendergast GC. Evidence that farnesyltransferase inhibitors suppress ras transformation by interfering with rho activity. Mol. Cell. Biol. 1995;15:6613–6622
  38. Du W, Lebowitz PF, Prendergast GC. Cell growth inhibition by farnesyltransferase inhibitors is mediated by gain of geranylgeranylated RhoB. Mol. Cell. Biol. 1999;19:1831–1840
  39. Chen Z, Sun J, Pradines A, Favre G, Adnane J, Sebti SM. Both farnesylated and geranylgeranylated RhoB inhibit malignant transformation, induce apoptosis and suppress human tumor growth in nude mice. J. Biol. Chem. 2000;275:17974–17978
  40. Johnston SR. Farnesyl transferase inhibitors: a novel targeted therapy for cancer. Lancet Oncol. 2001;2:18–26
  41. Haluska P, Dy GK, Adjei AA. Farnesyl transferase inhibitors as anticancer agents. Eur. J. Cancer. 2002;38:1685–1700
  42. Johnston SR, Kelland LR. Farnesyl transferase inhibitors—a novel therapy for breast cancer. Endocr. Relat. Cancer. 2001;8:227–235
  43. Cortes JE, Albitar M, Thomas D, Giles F, Kurzrock R, Thibault A, et al.  Efficacy of the farnesyl transferase inhibitor R115777 in chronic myeloid leukemia and other hematological malignancies. Blood. 2003;101:1692–1697
  44. Cloughesy T, Kuhn J, Wen P, Changh S, Schiff D, Greenberg I, et al.  Phase II trial of R115777 (Zarnestra) in patients with recurrent glioma not taking enzyme inducing antiepileptic drugs (EIAED): a North American Brain Tumor Consortium (NABTC) report. Proc. Am. Soc. Clin. Oncol. 2002;A317
  45. Cunningham D, De Gramont A, Scheithauer W, Smakal M, Humblet Y, Kurteva G, et al.  Randomized double-blind placebo-controlled trial of the farnseyltransferase inhibitor R115777 (Zarnestra) in advanced refractory colorectal cancer. Proc. Am. Soc. Clin. Oncol. 2002;A502
  46. Adjei AA, Davis JN, Erlichman C, Svingen PA, Kaufmann SH. Comparison of potential markers of farnesyltransferase inhibition. Clin. Cancer Res. 2000;6:2318–2325
  47. Du W, Liu A, Prendergast GC. Activation of the PI3′K-AKT pathway masks the proapoptotic effects of farnesyltransferase inhibitors. Cancer Res. 1999;59:4208–4212
  48. Sun J, Blaskovich MA, Knowles D, Qian Y, Ohkanda J, Bailey RD, et al.  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. Cancer Res. 1999;59:4919–4926
  49. Moasser MM, SeppLorenzino L, Kohl NE, Oliff A, Balog A, Su DS, et al.  Farnesyl transferase inhibitors cause enhanced mitotic sensitivity to taxol and epothilones. Proc. Natl. Acad. Sci. USA. 1998;95:1369–1374
  50. Sepp-Lorenzino L, Balog A, Su DS, Meng D, Timaul N, Scher HI, et al.  The microtubule-stabilizing agents epothilones A and B and their desoxy-derivatives induce mitotic arrest and apoptosis in human prostate cancer cells. Prostate Cancer Prostatic Dis. 1999;2:41–52
  51. Zhang B, Prendergast GC, Fenton RG. Farnesyltransferase inhibitors reverse Ras-mediated inhibition of Fas gene expression. Cancer Res. 2002;62:450–458
  52. Khuri F, Glisson B, Meyers M, Herbst R, Thall P, Munden R, et al.  Proc. Am. Soc. Clin. Oncol. 2000;A799
  53. Van Cutsem E, Karasek P, Oettle H, Vervenne W, Szawlowski A, Schoffski P, et al.  Phase III trial comparing gemcitabine+R115777 (Zarnestra) versus gemcitabine+placebo in advanced pancreatic cancer (PC). Proc. Am. Soc. Clin. Oncol. 2002;A517
  54. Cohen-Jonathan E, Toulas C, Ader I, Monteil S, Allal C, Bonnet J, et al.  The farnesyl transferase inhibitor FTI-277 suppresses the 24 kDa bFGF-induced radioresistance in HeLa cells expressing wild type Ras. Radiat. Res. 1999;152:404–411
  55. Bernhard EJ, McKenna WG, Hamilton AD, Sebti SM, Qian Y, Wu JM, et al. Inhibiting Ras prenylation increases the radiosensitivity of human tumor cell lines with activating mutations of ras oncogenes. Cancer Res. 1998;58:1754–1761
  56. Delmas C, Heliez C, Cohen-Jonathan E, End D, Bonnet J, Favre G, et al. The farnesyltransferase inhibitor, R115777, radiosensitizes radioresistant human glioma cell lines. Int. J. Cancer. 2002;100:43–48
  57. Cohen-Jonathan E, Evans SM, Koch CJ, Muschel RJ, McKenna WG, Wu J, et al. The farnesyltransferase inhibitor L744, 832 reduces hypoxia in tumors expressing activated H-ras. Cancer Res. 2001;61:2289–2293
  58. Hahn SM, Bernhard EJ, Regine W, Mohiuddin M, Haller DG, Stevenson JP, et al.  A Phase I trial of the farnesyltransferase inhibitor L-778, 123 and radiotherapy for locally advanced lung and head and neck cancer. Clin. Cancer Res. 2002;8:1065–1072
  59. End DW, Smets G, Todd AV, Applegate TL, Fuery CJ, Angibaud P, et al.  Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res. 2001;61:131–137
  60. Edamatsu H, Gau CL, Nemoto T, Guo L, Tamanoi F. Cdk inhibitors, roscovitine and olomoucine, synergize with farnesyltransferase inhibitor (FTI) to induce efficient apoptosis of human cancer cell lines. Oncogene. 2000;19:3059–3068
  61. Schwartz GK, O'Reilly E, Ilson D, Saltz L, Sharma S, Tong W, et al.  Phase I study of the cyclin-dependent kinase inhibitor flavopiridol in combination with paclitaxel in patients with advanced solid tumors. J. Clin. Oncol. 2002;20:2157–2170
  62. Hoover RR, Mahon FX, Melo JV, Daley GQ. Overcoming STI571 resistance with the farnesyl transferase inhibitor SCH66336. Blood. 2002;100:1068–1071
  63. Schwartz G, Rowinsky EK, Rha SY, Hammond LA, Smith L, Patnaik A, et al.  A Phase I, pharmacokinetic, and biologic correlative study of R115777 and trastuzumab (herceptin) in patients with advanced cancer. Proc. Am. Soc. Clin. Oncol. 2001;A322
  64. Su ZZ, Austin VN, Zimmer SG, Fisher PB. Defining the critical gene expression changes associated with expression and suppression of the tumorigenic and metastatic phenotype in Ha-ras-transformed cloned rat embryo fibroblast cells. Oncogene. 1993;8:1211–1219
  65. Sebti SM, Hamilton AD. Inhibition of Ras prenylation: a novel approach to cancer chemotherapy. Pharmacol. Ther. 1997;74:103–114
  66. Lobell RB, Omer CA, Abrams MT, Bhimnathwala HG, Brucker MJ, Buser CA, et al.  Evaluation of farnesyl:protein transferase and geranylgeranyl:protein transferase inhibitor combinations in preclinical models. Cancer Res. 2001;61:8758–8768
  67. Johnston SR, Head J, Pancholi S, Detre S, Martin LA, Smith IE, et al. Integration of signal transduction inhibitors with endocrine therapy: an approach to overcoming hormone resistance in breast cancer. Clin. Cancer Res. 2003;9:524S–532S
  68. Sepp-Lorenzino L, Tjaden G, Moasser MM, Timaul N, Ma Z, Kohl NE, et al.  Farnesyl:protein transferase inhibitors as potential agents for the management of human prostate cancer. Prostate Cancer Prostatic Dis. 2001;4:33–43

PII: S0304-3835(03)00635-9

doi: 10.1016/j.canlet.2003.08.033

Cancer Letters
Volume 206, Issue 2 , Pages 159-167 , 8 April 2004