© 2001 by Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 14, 1062-1074,
July 18, 2001
© 2001 Oxford University Press
REVIEW |
Blocking Oncogenic Ras Signaling for Cancer Therapy
Affiliations of author: Division of Medical Oncology Mayo Clinic and Foundation, Rochester, MN.
Correspondence to: Alex A. Adjei, M.D., Ph.D., Division of Medical Oncology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905 (e-mail: adjei.alex{at}mayo.edu).
The Ras gene product is a monomeric membrane-localized G protein of 21 kd that functions as a molecular switch linking receptor and nonreceptor tyrosine kinase activation to downstream cytoplasmic or nuclear events. Each mammalian cell contains at least three distinct ras proto-oncogenes encoding closely related, but distinct proteins. Activating mutations in these Ras proteins result in constitutive signaling, thereby stimulating cell proliferation and inhibiting apoptosis. Oncogenic mutations in the ras gene are present in approximately 30% of all human cancers. K-ras mutations occur frequently in non-small-cell lung, colorectal, and pancreatic carcinomas; H-ras mutations are common in bladder, kidney, and thyroid carcinomas; N-ras mutations are found in melanoma, hepatocellular carcinoma, and hematologic malignancies. The ras-signaling pathway has attracted considerable attention as a target for anticancer therapy because of its important role in carcinogenesis. In this review, the physiologic and biochemical properties of the Ras proteins, their mechanism of cell signaling, and their relation to human cancer will be discussed. Novel cancer therapeutic approaches based on the inhibition of Ras-mediated signaling, including inhibition of Ras processing, inhibition of Ras protein synthesis, and blockage of downstream Ras effectors, will be discussed.
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K.-H. Chun, H.-Y. Lee, K. Hassan, F. Khuri, W. K. Hong, and R. Lotan Implication of Protein Kinase B/Akt and Bcl-2/Bcl-XL Suppression by the Farnesyl Transferase Inhibitor SCH66336 in Apoptosis Induction in Squamous Carcinoma Cells Cancer Res., August 15, 2003; 63(16): 4796 - 4800. [Abstract] [Full Text] [PDF]
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M. P. Goetz, D. O. Toft, M. M. Ames, and C. Erlichman The Hsp90 chaperone complex as a novel target for cancer therapy Ann. Onc., August 1, 2003; 14(8): 1169 - 1176. [Abstract] [Full Text] [PDF]
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B. Zhang, A. Ougolkov, K. Yamashita, Y. Takahashi, M. Mai, and T. Minamoto {beta}-Cateninand ras Oncogenes Detect Most Human Colorectal Cancer Clin. Cancer Res., August 1, 2003; 9(8): 3073 - 3079. [Abstract] [Full Text] [PDF]
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M. Eskandarpour, J. Hashemi, L. Kanter, U. Ringborg, A. Platz, and J. Hansson Frequency of UV-Inducible NRAS Mutations in Melanomas of Patients With Germline CDKN2A Mutations J Natl Cancer Inst, June 4, 2003; 95(11): 790 - 798. [Abstract] [Full Text] [PDF]
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A. M. Winter-Vann, B. A. Kamen, M. O. Bergo, S. G. Young, S. Melnyk, S. J. James, and P. J. Casey Targeting Ras signaling through inhibition of carboxyl methylation: An unexpected property of methotrexate PNAS, May 27, 2003; 100(11): 6529 - 6534. [Abstract] [Full Text] [PDF]
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E. K. Rowinsky Challenges of Developing Therapeutics That Target Signal Transduction in Patients With Gynecologic and Other Malignancies J. Clin. Oncol., May 15, 2003; 21(90100): 175s - 186. [Abstract] [Full Text] [PDF]
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A. A. Adjei, A. Mauer, L. Bruzek, R. S. Marks, S. Hillman, S. Geyer, L. J. Hanson, J. J. Wright, C. Erlichman, S. H. Kaufmann, et al. Phase II Study of the Farnesyl Transferase Inhibitor R115777 in Patients With Advanced Non-Small-Cell Lung Cancer J. Clin. Oncol., May 1, 2003; 21(9): 1760 - 1766. [Abstract] [Full Text] [PDF]
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J. Cortes, M. Albitar, D. Thomas, F. Giles, R. Kurzrock, A. Thibault, W. Rackoff, C. Koller, S. O'Brien, G. Garcia-Manero, et al. Efficacy of the farnesyl transferase inhibitor R115777 in chronic myeloid leukemia and other hematologic malignancies Blood, March 1, 2003; 101(5): 1692 - 1697. [Abstract] [Full Text] [PDF]
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H. Kawasaki, E. Suyama, M. Iyo, and K. Taira siRNAs generated by recombinant human Dicer induce specific and significant but target site-independent gene silencing in human cells Nucleic Acids Res., February 1, 2003; 31(3): 981 - 987. [Abstract] [Full Text] [PDF]
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F. Ravandi, M. Talpaz, and Z. Estrov Modulation of Cellular Signaling Pathways: Prospects for Targeted Therapy in Hematological Malignancies Clin. Cancer Res., February 1, 2003; 9(2): 535 - 550. [Abstract] [Full Text] [PDF]
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F. G. El Kamar, M. L. Grossbard, and P. S. Kozuch Metastatic Pancreatic Cancer: Emerging Strategies in Chemotherapy and Palliative Care Oncologist, February 1, 2003; 8(1): 18 - 34. [Abstract] [Full Text] [PDF]
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P. Russo, D. Arzani, S. Trombino, and C. Falugi c-myc Down-Regulation Induces Apoptosis in Human Cancer Cell Lines Exposed to RPR-115135 (C31H29NO4), a Non-Peptidomimetic Farnesyltransferase Inhibitor J. Pharmacol. Exp. Ther., January 1, 2003; 304(1): 37 - 47. [Abstract] [Full Text] [PDF]
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T. Portis and R. Longnecker Epstein-Barr Virus LMP2A Interferes with Global Transcription Factor Regulation When Expressed during B-Lymphocyte Development J. Virol., December 6, 2002; 77(1): 105 - 114. [Abstract] [Full Text] [PDF]
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B. K. Law, A. Chytil, N. Dumont, E. G. Hamilton, M. E. Waltner-Law, M. E. Aakre, C. Covington, and H. L. Moses Rapamycin Potentiates Transforming Growth Factor {beta}-Induced Growth Arrest in Nontransformed, Oncogene-Transformed, and Human Cancer Cells Mol. Cell. Biol., December 1, 2002; 22(23): 8184 - 8198. [Abstract] [Full Text] [PDF]
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M. S. Brose, P. Volpe, M. Feldman, M. Kumar, I. Rishi, R. Gerrero, E. Einhorn, M. Herlyn, J. Minna, A. Nicholson, et al. BRAF and RAS Mutations in Human Lung Cancer and Melanoma Cancer Res., December 1, 2002; 62(23): 6997 - 7000. [Abstract] [Full Text] [PDF]
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J. Pinkas and P. Leder MEK1 Signaling Mediates Transformation and Metastasis of EpH4 Mammary Epithelial Cells Independent of an Epithelial to Mesenchymal Transition Cancer Res., August 15, 2002; 62(16): 4781 - 4790. [Abstract] [Full Text] [PDF]
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S. Canevari, S. Biocca, and M. Figini Re: Blocking Oncogenic Ras Signaling for Cancer Therapy J Natl Cancer Inst, July 3, 2002; 94(13): 1031 - 1032. [Full Text] [PDF]
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G. K. Dy and A. A. Adjei Novel Targets for Lung Cancer Therapy: Part I J. Clin. Oncol., June 15, 2002; 20(12): 2881 - 2894. [Abstract] [Full Text] [PDF]
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C. J. Barnes, F. Li, M. Mandal, Z. Yang, A. A. Sahin, and R. Kumar Heregulin Induces Expression, ATPase Activity, and Nuclear Localization of G3BP, a Ras Signaling Component, in Human Breast Tumors Cancer Res., March 1, 2002; 62(5): 1251 - 1255. [Abstract] [Full Text] [PDF]
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H. J. Varghese, M. T. M. Davidson, I. C. MacDonald, S. M. Wilson, K. V. Nadkarni, A. C. Groom, and A. F. Chambers Activated Ras Regulates the Proliferation/Apoptosis Balance and Early Survival of Developing Micrometastases Cancer Res., February 1, 2002; 62(3): 887 - 891. [Abstract] [Full Text] [PDF]
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