Cancer targets in the Ras pathway.

Ras proteins play a direct causal role in human cancer and in other diseases. Mutant H-Ras, N-Ras, and K-Ras occur in varying frequencies in different tumor types, for reasons that are not known. Other members of the Ras superfamily may also contribute to cancer. Mutations also occur in downstream pathways, notably B-Raf, PTEN, and PI 3' kinase: These pathways interact at multiple points, including cyclin D1, and act synergistically. In some cases mutations in Ras and effectors are mutually exclusive; in other cases, they coexist. Drugs blocking elements of the pathway are in different stages of clinical development. One of these, the Raf kinase/VEGF-R2 inhibitor Sorafenib, has already been approved for treatment of renal cancer and is being tested in other indications. However, therapeutic targets in the Ras pathway have not yet been fully validated as bona fide targets.

[1]  R. Kucherlapati,et al.  K-ras is an essential gene in the mouse with partial functional overlap with N-ras. , 1997, Genes & development.

[2]  D. Auclair,et al.  BAY 43-9006 Exhibits Broad Spectrum Oral Antitumor Activity and Targets the RAF/MEK/ERK Pathway and Receptor Tyrosine Kinases Involved in Tumor Progression and Angiogenesis , 2004, Cancer Research.

[3]  Chris Albanese,et al.  NF-κB Controls Cell Growth and Differentiation through Transcriptional Regulation of Cyclin D1 , 1999, Molecular and Cellular Biology.

[4]  M. Malumbres,et al.  Targeted Genomic Disruption of H-ras and N-ras, Individually or in Combination, Reveals the Dispensability of Both Loci for Mouse Growth and Development , 2001, Molecular and Cellular Biology.

[5]  C. Albanese,et al.  Transforming p21ras Mutants and c-Ets-2 Activate the Cyclin D1 Promoter through Distinguishable Regions (*) , 1995, The Journal of Biological Chemistry.

[6]  Claus Scheidereit,et al.  NF-κB Function in Growth Control: Regulation of Cyclin D1 Expression and G0/G1-to-S-Phase Transition , 1999, Molecular and Cellular Biology.

[7]  W. Kabsch,et al.  Guanosine triphosphatase stimulation of oncogenic Ras mutants. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[8]  Frank Petersen,et al.  Small-molecule antagonists of the oncogenic Tcf/β-catenin protein complex , 2004 .

[9]  E. Zackai,et al.  HRAS mutation analysis in Costello syndrome: Genotype and phenotype correlation , 2006, American journal of medical genetics. Part A.

[10]  M. Teitell,et al.  Mutations in Costello Syndrome : Detection of Constitutional Activating Mutations in Codon 12 and 13 and Loss of Wild-Type Allele in Malignancy , 2005 .

[11]  D. Pinkel,et al.  Genomic approaches to skin cancer diagnosis. , 2001, Archives of dermatology.

[12]  C. Albanese,et al.  Epidermal Growth Factor and c-Jun Act via a Common DNA Regulatory Element to Stimulate Transcription of the Ovine P-450 Cholesterol Side Chain Cleavage (CYP11A1) Promoter (*) , 1995, The Journal of Biological Chemistry.

[13]  Frank McCormick,et al.  High frequency of coexistent mutations of PIK3CA and PTEN genes in endometrial carcinoma. , 2005, Cancer research.

[14]  Frank McCormick,et al.  The GTPase superfamily: conserved structure and molecular mechanism , 1991, Nature.

[15]  W. Reardon,et al.  Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases , 2005, Journal of Medical Genetics.

[16]  A. Nicholson,et al.  Mutations of the BRAF gene in human cancer , 2002, Nature.

[17]  L. Augenlicht,et al.  Cyclin D1 Genetic Heterozygosity Regulates Colonic Epithelial Cell Differentiation and Tumor Number in ApcMin Mice , 2004, Molecular and Cellular Biology.

[18]  Kam Y. J. Zhang,et al.  Germline KRAS mutations cause Noonan syndrome , 2006, Nature Genetics.

[19]  E. Pai,et al.  The structure of Ras protein: a model for a universal molecular switch. , 1991, Trends in biochemical sciences.

[20]  F. McCormick,et al.  Signaling Specificity by Ras Family GTPases Is Determined by the Full Spectrum of Effectors They Regulate , 2004, Molecular and Cellular Biology.

[21]  Yukichi Tanaka,et al.  Germline mutations in HRAS proto-oncogene cause Costello syndrome , 2005, Nature Genetics.

[22]  E. Bossy‐Wetzel,et al.  Cell cycle‐dependent variations in c‐Jun and JunB phosphorylation: a role in the control of cyclin D1 expression , 2000, The EMBO journal.

[23]  Pablo Rodriguez-Viciana,et al.  Germline Mutations in Genes Within the MAPK Pathway Cause Cardio-facio-cutaneous Syndrome , 2006, Science.

[24]  Frank McCormick,et al.  β-Catenin regulates expression of cyclin D1 in colon carcinoma cells , 1999, Nature.