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[Cancer Research 55, 5302-5309, November 15, 1995]
© 1995 American Association for Cancer Research
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A Peptidomimetic Inhibitor of Farnesyl:Protein Transferase Blocks the Anchorage-dependent and -independent Growth of Human Tumor Cell Lines1

Laura Sepp-Lorenzino, Zhenping Ma, Elaine Rands, Nancy E. Kohl, Jackson B. Gibbs, Allen Oliff and Neal Rosen2

Program in Cell Biology and Genetics and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021 [L. S-L., Z. M., N. R.], and Department of Cancer Research, Merck Research Laboratories, West Point, Pennsylvania 19486 [E. R., N. E. K., J. B. G., A. O.]

Farnesyl protein transferase (FPTase) catalyzes the first of a series of posttranslational modifications of Ras required for full biological activity. Peptidomimetic inhibitors of FPTase have been designed that selectively block farnesylation in vivo and in vitro. These inhibitors prevent Ras processing and membrane localization and are effective in reversing the transformed phenotype of Rat1-v-ras cells but not that of cells transformed by v-raf or v-mos. We have tested the effect of the FPTase inhibitor L-744,832 (FTI) on the anchorage-dependent and -independent growth of human tumor cell lines. The growth of over 70% of all tumor cell lines tested was inhibited by 2–20 µM of the FTI, whereas the anchorage-dependent growth of nontransformed epithelial cells was less sensitive to the effects of the compound. No correlation was observed between response to drug and the origin of the tumor cell or whether it contained mutationally activated ras. In fact, cell lines with wild-type ras and active protein tyrosine kinases in which the transformed phenotype may depend on upstream activation of the ras pathway were especially sensitive to the drug. To define the important targets of FTI action, the mechanism of cellular drug resistance was examined. It was not a function of altered drug accumulation or of FPTase insensitivity since, in all cell lines tested, FPTase activity was readily inhibited within 1 h of treatment with the inhibitor. Furthermore, the general pattern of inhibition of cellular protein farnesylation and the specific inhibition of lamin B processing were the same in sensitive and resistant cells. In addition, functional activation of Ras was inhibited to the same degree in sensitive and resistant cell lines. However, the FTI inhibited the epidermal growth factor-induced activation of mitogen-activated protein kinases in sensitive cells but not in two resistant cell lines. These data suggest that the drug does inhibit ras function and that resistance in some cells is associated with the presence of Ras-independent pathways for mitogen-activated protein kinase activation by tyrosine kinases. We conclude that FPTase inhibitors are potent antitumor agents with activity against many types of human cancer cell lines, including those with wild-type ras.

1 Supported in part by the National Cancer Institute of the NIH, Grant CA 58706-01 (to N. R.).

2 To whom requests for reprints should be addressed, at Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 271, New York, NY 10021. Phone: (212) 639-2369; Fax: (212) 717-3627.

Received 6/22/95. Accepted 9/19/95.




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Farnesyltransferase Inhibitor Induces Rapid Growth Arrest and Blocks p70s6k Activation by Multiple Stimuli
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A Phase I Trial of the Farnesyl Transferase Inhibitor SCH66336: Evidence for Biological and Clinical Activity
Cancer Res., April 1, 2000; 60(7): 1871 - 1877.
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J. Zujewski, I. D. Horak, C. J. Bol, R. Woestenborghs, C. Bowden, D. W. End, V. K. Piotrovsky, J. Chiao, R. T. Belly, A. Todd, et al.
Phase I and Pharmacokinetic Study of Farnesyl Protein Transferase Inhibitor R115777 in Advanced Cancer
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S.-C. J. Yeung, G. Xu, J. Pan, M. Christgen, and A. Bamiagis
Manumycin Enhances the Cytotoxic Effect of Paclitaxel on Anaplastic Thyroid Carcinoma Cells
Cancer Res., February 1, 2000; 60(3): 650 - 656.
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P. D. Emanuel, R. C. Snyder, T. Wiley, B. Gopurala, and R. P. Castleberry
Inhibition of juvenile myelomonocytic leukemia cell growth in vitro by farnesyltransferase inhibitors
Blood, January 15, 2000; 95(2): 639 - 645.
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W. Yang, J. Urano, and F. Tamanoi
Protein Farnesylation Is Critical for Maintaining Normal Cell Morphology and Canavanine Resistance in Schizosaccharomyces pombe
J. Biol. Chem., January 7, 2000; 275(1): 429 - 438.
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L. E. Lantry, Z. Zhang, R. Yao, K. A. Crist, Y. Wang, J. Ohkanda, A. D. Hamilton, S. M. Sebti, R. A. Lubet, and M. You
Effect of farnesyltransferase inhibitor FTI-276 on established lung adenomas from A/J mice induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
Carcinogenesis, January 1, 2000; 21(1): 113 - 116.
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E. K. Rowinsky, J. J. Windle, and D. D. Von Hoff
Ras Protein Farnesyltransferase: A Strategic Target for Anticancer Therapeutic Development
J. Clin. Oncol., November 1, 1999; 17(11): 3631 - 3652.
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W. Du and G. C. Prendergast
Geranylgeranylated RhoB Mediates Suppression of Human Tumor Cell Growth by Farnesyltransferase Inhibitors
Cancer Res., November 1, 1999; 59(21): 5492 - 5496.
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J. Sun, M. A. Blaskovich, D. Knowles, Y. Qian, J. Ohkanda, R. D. Bailey, A. D. Hamilton, and S. M. Sebti
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., October 1, 1999; 59(19): 4919 - 4926.
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N. Mahgoub, B. R. Taylor, M. Gratiot, N. E. Kohl, J. B. Gibbs, T. Jacks, and K. M. Shannon
In Vitro and In Vivo Effects of a Farnesyltransferase Inhibitor on Nf1-Deficient Hematopoietic Cells
Blood, October 1, 1999; 94(7): 2469 - 2476.
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K. Del Villar, J. Urano, L. Guo, and F. Tamanoi
A Mutant Form of Human Protein Farnesyltransferase Exhibits Increased Resistance to Farnesyltransferase Inhibitors
J. Biol. Chem., September 17, 1999; 274(38): 27010 - 27017.
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W. Du, A. Liu, and G. C. Prendergast
Activation of the PI3'K-AKT Pathway Masks the Proapoptotic Effects of Farnesyltransferase Inhibitors
Cancer Res., September 1, 1999; 59(17): 4208 - 4212.
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W. Du, P. F. Lebowitz, and G. C. Prendergast
Elevation of {{alpha}}2(I) Collagen, a Suppressor of Ras Transformation, Is Required for Stable Phenotypic Reversion by Farnesyltransferase Inhibitors
Cancer Res., May 1, 1999; 59(9): 2059 - 2063.
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M. Kretzschmar, J. Doody, I. Timokhina, and J. Massagué
A mechanism of repression of TGFbeta / Smad signaling by oncogenic Ras
Genes & Dev., April 1, 1999; 13(7): 804 - 816.
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 Mol. Cell. Biol.Home page
W. Du, P. F. Lebowitz, and G. C. Prendergast
Cell Growth Inhibition by Farnesyltransferase Inhibitors Is Mediated by Gain of Geranylgeranylated RhoB
Mol. Cell. Biol., March 1, 1999; 19(3): 1831 - 1840.
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B. K. Law, P. Norgaard, L. Gnudi, B. B. Kahn, H. S. Poulson, and H. L. Moses
Inhibition of DNA Synthesis by a Farnesyltransferase Inhibitor Involves Inhibition of the p70s6k Pathway
J. Biol. Chem., February 19, 1999; 274(8): 4743 - 4748.
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 Clin. Cancer Res.Home page
P. Norgaard, B. Law, H. Joseph, D. L. Page, Y. Shyr, D. Mays, J. A. Pietenpol, N. E. Kohl, A. Oliff, R. J. Coffey Jr., et al.
Treatment with Farnesyl-Protein Transferase Inhibitor Induces Regression of Mammary Tumors in Transforming Growth Factor (TGF) {{alpha}} and TGF{{alpha}}/neu Transgenic Mice by Inhibition of Mitogenic Activity and Induction of Apoptosis
Clin. Cancer Res., January 1, 1999; 5(1): 35 - 42.
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 Proc. Natl. Acad. Sci. USAHome page
N. Suzuki, J. Urano, and F. Tamanoi
Farnesyltransferase inhibitors induce cytochrome c release and caspase 3 activation preferentially in transformed cells
PNAS, December 22, 1998; 95(26): 15356 - 15361.
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T. E. Graham, J. R. Pfeiffer, R. J. Lee, D. F. Kusewitt, A. M. Martinez, T. Foutz, B. S. Wilson, and J. M. Oliver
MEK and ERK Activation in Ras-Disabled RBL-2H3 Mast Cells and Novel Roles for Geranylgeranylated and Farnesylated Proteins in Fc{epsilon}RI-Mediated Signaling
J. Immunol., December 15, 1998; 161(12): 6733 - 6744.
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N. Suzuki, K. Del Villar, and F. Tamanoi
Farnesyltransferase inhibitors induce dramatic morphological changes of KNRK cells that are blocked by microtubule interfering agents
PNAS, September 1, 1998; 95(18): 10499 - 10504.
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L. Sepp-Lorenzino and N. Rosen
A Farnesyl-Protein Transferase Inhibitor Induces p21 Expression and G1 Block in p53 Wild Type Tumor Cells
J. Biol. Chem., August 7, 1998; 273(32): 20243 - 20251.
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M. Yonemoto, T. Satoh, H. Arakawa, I. Suzuki-Takahashi, Y. Monden, T. Kodera, K. Tanaka, T. Aoyama, Y. Iwasawa, T. Kamei, et al.
J-104,871, a Novel Farnesyltransferase Inhibitor, Blocks Ras Farnesylation In Vivo in a Farnesyl Pyrophosphate-Competitive Manner
Mol. Pharmacol., July 1, 1998; 54(1): 1 - 7.
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M. M. Moasser, L. Sepp-Lorenzino, N. E. Kohl, A. Oliff, A. Balog, D.-S. Su, S. J. Danishefsky, and N. Rosen
Farnesyl transferase inhibitors cause enhanced mitotic sensitivity to taxol and epothilones
PNAS, February 17, 1998; 95(4): 1369 - 1374.
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 Mol. Cell. Biol.Home page
R. E. Barrington, M. A. Subler, E. Rands, C. A. Omer, P. J. Miller, J. E. Hundley, S. K. Koester, D. A. Troyer, D. J. Bearss, M. W. Conner, 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., January 1, 1998; 18(1): 85 - 92.
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A. M. Kral, R. E. Diehl, S. J. deSolms, T. M. Williams, N. E. Kohl, and C. A. Omer
Mutational Analysis of Conserved Residues of the beta -Subunit of Human Farnesyl:Protein Transferase
J. Biol. Chem., October 24, 1997; 272(43): 27319 - 27323.
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 Proc. Natl. Acad. Sci. USAHome page
C. E. Trueblood, V. L. Boyartchuk, and J. Rine
Substrate specificity determinants in the farnesyltransferase beta -subunit
PNAS, September 30, 1997; 94(20): 10774 - 10779.
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M. Arico, A. Biondi, and C.-H. Pui
Juvenile Myelomonocytic Leukemia
Blood, July 15, 1997; 90(2): 479 - 488.
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P. F. Lebowitz, P. J. Casey, G. C. Prendergast, and J. A. Thissen
Farnesyltransferase Inhibitors Alter the Prenylation and Growth-stimulating Function of RhoB
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M. Raiteri, L. Arnaboldi, P. Mcgeady, M. H. Gelb, D. Verri, C. Tagliabue, P. Quarato, P. Ferraboschi, E. Santaniello, R. Paoletti, et al.

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K- and N-Ras Are Geranylgeranylated in Cells Treated with Farnesyl Protein Transferase Inhibitors
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F. L. Zhang, P. Kirschmeier, D. Carr, L. James, R. W. Bond, L. Wang, R. Patton, W. T. Windsor, R. Syto, R. Zhang, et al.
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
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F. Ventura, F. Liu, J. Doody, and J. Massague
Interaction of Transforming Growth Factor-beta Receptor I with Farnesyl-protein Transferase-alpha in Yeast and Mammalian Cells
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P. J. Casey and M. C. Seabra
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H. R. Ashar, L. James, K. Gray, D. Carr, S. Black, L. Armstrong, W. R. Bishop, and P. Kirschmeier
Farnesyl Transferase Inhibitors Block the Farnesylation of CENP-E and CENP-F and Alter the Association of CENP-E with the Microtubules
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N. C. Crespo, J. Ohkanda, T. J. Yen, A. D. Hamilton, and S. M. Sebti
The Farnesyltransferase Inhibitor, FTI-2153, Blocks Bipolar Spindle Formation and Chromosome Alignment and Causes Prometaphase Accumulation during Mitosis of Human Lung Cancer Cells
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S. B. Long, P. J. Hancock, A. M. Kral, H. W. Hellinga, and L. S. Beese
The crystal structure of human protein farnesyltransferase reveals the basis for inhibition by CaaX tetrapeptides and their mimetics
PNAS, November 6, 2001; 98(23): 12948 - 12953.
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