This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sridhar, S. S. Articles by Siu, L. L. Search for Related Content PubMed PubMed Citation Articles by Sridhar, S. S. Articles by Siu, L. L. Related Collections Therapeutics and Targets Therapeutics and Targets: Identification, Validation, and Markers

Minireview

Raf kinase as a target for anticancer therapeutics

Department of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada

Requests for reprints: Lillian L. Siu, Department of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, 610 University Avenue, Suite 5-210, Toronto, Ontario, Canada M5G 2M9. Phone: 416-946-2911; Fax: 416-946-6546. E-mail: lillian.siu{at}uhn.on.ca

The Ras-Raf-MEK-ERK (ERK) pathway is a logical therapeutic target because it represents a common downstream pathway for several key growth factor tyrosine kinase receptors which are often mutated or overexpressed in human cancers. Although considered mainly growth-promoting, in certain contexts, this pathway also seems to be apoptosis-suppressing. Several novel agents targeting this pathway have now been developed and are in clinical trials. One of the most interesting new agents is BAY 43-9006. Although initially developed as a Raf kinase inhibitor, it can also target several other important tyrosine kinases including VEGFR-2, Flt-3, and c-Kit, which contributes to its antiproliferative and antiangiogenic properties. To date, encouraging results have been seen with BAY 43-9006, particularly in renal cell cancers which are highly vascular tumors. This review will provide an overview of the ERK signaling pathway in normal and neoplastic tissue, with a specific focus on novel therapies targeting the ERK pathway at the level of Raf kinase.

Key Words: Raf kinase • signal transduction • molecular targeting

Received 11/ 3/04; revised 1/20/05; accepted 2/15/05.

This article has been cited by other articles:

				D. W. Chan, V. W.S. Liu, G. S.W. Tsao, K.-M. Yao, T. Furukawa, K. K.L. Chan, and H. Y.S. Ngan Loss of MKP3 mediated by oxidative stress enhances tumorigenicity and chemoresistance of ovarian cancer cells Carcinogenesis, September 1, 2008; 29(9): 1742 - 1750. [Abstract] [Full Text] [PDF]

				J. Borlak and H. S. Jenke Cross-talk between Aryl Hydrocarbon Receptor and Mitogen-Activated Protein Kinase Signaling Pathway in Liver Cancer through c-raf Transcriptional Regulation Mol. Cancer Res., August 1, 2008; 6(8): 1326 - 1336. [Abstract] [Full Text] [PDF]

				L. Dal Lago, V. D'Hondt, and A. Awada Selected Combination Therapy with Sorafenib: A Review of Clinical Data and Perspectives in Advanced Solid Tumors Oncologist, August 1, 2008; 13(8): 845 - 858. [Abstract] [Full Text] [PDF]

				R. Kinkade, P. Dasgupta, A. Carie, D. Pernazza, M. Carless, S. Pillai, N. Lawrence, S. M. Sebti, and S. Chellappan A Small Molecule Disruptor of Rb/Raf-1 Interaction Inhibits Cell Proliferation, Angiogenesis, and Growth of Human Tumor Xenografts in Nude Mice Cancer Res., May 15, 2008; 68(10): 3810 - 3818. [Abstract] [Full Text] [PDF]

				G. Ambrosini, H. S. Cheema, S. Seelman, A. Teed, E. B. Sambol, S. Singer, and G. K. Schwartz Sorafenib inhibits growth and mitogen-activated protein kinase signaling in malignant peripheral nerve sheath cells Mol. Cancer Ther., April 1, 2008; 7(4): 890 - 896. [Abstract] [Full Text] [PDF]

				T. Helikar, J. Konvalina, J. Heidel, and J. A. Rogers Emergent decision-making in biological signal transduction networks PNAS, February 12, 2008; 105(6): 1913 - 1918. [Abstract] [Full Text] [PDF]

				A. A. Garcia Small Molecules: Big Changes in the Cancer Treatment Paradigm Journal of Pharmacy Practice, February 1, 2008; 21(1): 17 - 35. [Abstract] [PDF]

				H. Huynh, P. K.H. Chow, and K.-C. Soo AZD6244 and doxorubicin induce growth suppression and apoptosis in mouse models of hepatocellular carcinoma Mol. Cancer Ther., September 1, 2007; 6(9): 2468 - 2476. [Abstract] [Full Text] [PDF]

				C. Elser, L. L. Siu, E. Winquist, M. Agulnik, G. R. Pond, S. F. Chin, P. Francis, R. Cheiken, J. Elting, A. McNabola, et al. Phase II Trial of Sorafenib in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck or Nasopharyngeal Carcinoma J. Clin. Oncol., August 20, 2007; 25(24): 3766 - 3773. [Abstract] [Full Text] [PDF]

				I. Duran, S. J. Hotte, H. Hirte, E. X. Chen, M. MacLean, S. Turner, L. Duan, G. R. Pond, C. Lathia, S. Walsh, et al. Phase I Targeted Combination Trial of Sorafenib and Erlotinib in Patients with Advanced Solid Tumors Clin. Cancer Res., August 15, 2007; 13(16): 4849 - 4857. [Abstract] [Full Text] [PDF]

				L. A. Fecher, S. D. Cummings, M. J. Keefe, and R. M. Alani Toward a Molecular Classification of Melanoma J. Clin. Oncol., April 20, 2007; 25(12): 1606 - 1620. [Abstract] [Full Text] [PDF]

				N. Steeghs, J. W. R. Nortier, and H. Gelderblom Small Molecule Tyrosine Kinase Inhibitors in the Treatment of Solid Tumors: An Update of Recent Developments Ann. Surg. Oncol., February 1, 2007; 14(2): 942 - 953. [Abstract] [Full Text] [PDF]

				E. P. Jane, D. R. Premkumar, and I. F. Pollack Coadministration of Sorafenib with Rottlerin Potently Inhibits Cell Proliferation and Migration in Human Malignant Glioma Cells J. Pharmacol. Exp. Ther., December 1, 2006; 319(3): 1070 - 1080. [Abstract] [Full Text] [PDF]

				M. V. Cespedes, F. J. Sancho, S. Guerrero, M. Parreno, I. Casanova, M. A. Pavon, E. Marcuello, M. Trias, M. Cascante, G. Capella, et al. K-ras Asp12 mutant neither interacts with Raf, nor signals through Erk and is less tumorigenic than K-ras Val12 Carcinogenesis, November 1, 2006; 27(11): 2190 - 2200. [Abstract] [Full Text] [PDF]

				F. Lang, C. Bohmer, M. Palmada, G. Seebohm, N. Strutz-Seebohm, and V. Vallon (Patho)physiological Significance of the Serum- and Glucocorticoid-Inducible Kinase Isoforms. Physiol Rev, October 1, 2006; 86(4): 1151 - 1178. [Abstract] [Full Text] [PDF]

				C. Yu, B. B. Friday, J.-P. Lai, L. Yang, J. Sarkaria, N. E. Kay, C. A. Carter, L. R. Roberts, S. H. Kaufmann, and A. A. Adjei Cytotoxic synergy between the multikinase inhibitor sorafenib and the proteasome inhibitor bortezomib in vitro: induction of apoptosis through Akt and c-Jun NH2-terminal kinase pathways. Mol. Cancer Ther., September 1, 2006; 5(9): 2378 - 2387. [Abstract] [Full Text] [PDF]

				D. H. Johnson Targeted therapies in combination with chemotherapy in non-small cell lung cancer. Clin. Cancer Res., July 15, 2006; 12(14): 4451s - 4457s. [Abstract] [Full Text] [PDF]

				Y. Newbatt, S. Burns, R. Hayward, S. Whittaker, R. Kirk, C. Marshall, C. Springer, E. Mcdonald, Cancer Genome Project, R. Marais, et al. Identification of Inhibitors of the Kinase Activity of Oncogenic V600EBRAF in an Enzyme Cascade High-Throughput Screen J Biomol Screen, March 1, 2006; 11(2): 145 - 154. [Abstract] [PDF]

				K. P. Hoeflich, D. C. Gray, M. T. Eby, J. Y. Tien, L. Wong, J. Bower, A. Gogineni, J. Zha, M. J. Cole, H. M. Stern, et al. Oncogenic BRAF Is Required for Tumor Growth and Maintenance in Melanoma Models Cancer Res., January 15, 2006; 66(2): 999 - 1006. [Abstract] [Full Text] [PDF]

				Y. Chen, D. E. Feldman, C. Deng, J. A. Brown, A. F. De Giacomo, A. F. Gaw, G. Shi, Q. T. Le, J. M. Brown, and A. C. Koong Identification of Mitogen-Activated Protein Kinase Signaling Pathways That Confer Resistance to Endoplasmic Reticulum Stress in Saccharomyces cerevisiae Mol. Cancer Res., December 1, 2005; 3(12): 669 - 677. [Abstract] [Full Text] [PDF]

				M. Rahmani, E. M. Davis, C. Bauer, P. Dent, and S. Grant Apoptosis Induced by the Kinase Inhibitor BAY 43-9006 in Human Leukemia Cells Involves Down-regulation of Mcl-1 through Inhibition of Translation J. Biol. Chem., October 21, 2005; 280(42): 35217 - 35227. [Abstract] [Full Text] [PDF]