Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status.
Harith Rajagopalan,Alberto Bardelli,Christoph Lengauer,Kenneth W. Kinzler,Bert Vogelstein,Victor E. Velculescu +5 more
TLDR
The results not only provide genetic support for the idea that mutations in BRAF and KRAS exert equivalent effects in tumorigenesis, but also emphasize the role of repair processes in establishing the mutation spectra that underpin human cancer.Abstract:
Genes of the RAF family encode kinases that are regulated by Ras and mediate cellular responses to growth signals. Activating mutations in one RAF gene, BRAF, have been found in a high proportion of melanomas and in a small fraction of other cancers. Here we show that BRAF mutations in colorectal cancers occur only in tumours that do not carry mutations in a RAS gene known as KRAS, and that BRAF mutation is linked to the proficiency of these tumours in repairing mismatched bases in DNA. Our results not only provide genetic support for the idea that mutations in BRAF and KRAS exert equivalent effects in tumorigenesis, but also emphasize the role of repair processes in establishing the mutation spectra that underpin human cancer.read more
Citations
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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
Scott Wilhelm,Christopher A. Carter,LiYa Tang,Dean Wilkie,Angela McNabola,Hong Rong,Charles Chen,Xiaomei Zhang,Patrick Vincent,Mark McHugh,Yichen Cao,Jaleel Shujath,Susan Gawlak,Deepa Eveleigh,Bruce Rowley,Li Liu,Lila Adnane,Mark Lynch,Daniel Auclair,Ian W. Taylor,Rich Gedrich,Andrei Voznesensky,Bernd Riedl,Leonard Post,Gideon Bollag,Pamela A. Trail +25 more
TL;DR: Data demonstrate that BAY 43-9006 is a novel dual action RAF kinase and VEGFR inhibitor that targets tumor cell proliferation and tumor angiogenesis.
Journal ArticleDOI
Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer.
TL;DR: The current status of the different approaches and targets that are under evaluation and development for the therapeutic intervention of this key signaling pathway in human disease are summarized.
Journal ArticleDOI
Mechanism of Activation of the Raf-Erk Signaling Pathway by Oncogenic Mutations of B-Raf
Paul T C Wan,Mathew J. Garnett,S. Mark Roe,Sharlene Lee,Dan Niculescu-Duvaz,Valerie M. Good,Cancer Genome,C. Michael Jones,Christopher J. Marshall,Caroline J. Springer,David Barford,Richard Marais +11 more
TL;DR: The high activity mutants signal to ERK by directly phosphorylating MEK, whereas the impaired activity mutants stimulate MEK by activating endogenous C-RAF, possibly via an allosteric or transphosphorylation mechanism.
Journal ArticleDOI
Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability.
TL;DR: This work surmises that CRI represents the seventh hallmark of cancer, and suggests that an additional mechanism involved in cancer-related inflammation (CRI) is induction of genetic instability by inflammatory mediators, leading to accumulation of random genetic alterations in cancer cells.
Journal ArticleDOI
Roles of the raf/mek/erk pathway in cell growth, malignant transformation and drug resistance
James A. McCubrey,Linda S. Steelman,William H. Chappell,Stephen L. Abrams,Ellis W.T. Wong,Fumin Chang,Brian D. Lehmann,David M. Terrian,Michele Milella,Agostino Tafuri,Franca Stivala,Massimo Libra,Jörg Bäsecke,Camilla Evangelisti,Alberto M. Martelli,Richard A. Franklin +15 more
TL;DR: The Raf/MEK/ERK pathway has different effects on growth, prevention of apoptosis, cell cycle arrest and induction of drug resistance in cells of various lineages which may be due to the presence of functional p53 and PTEN and the expression of lineage specific factors.
References
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Journal ArticleDOI
Mutations of the BRAF gene in human cancer
Helen Davies,Graham R. Bignell,Charles Cox,Philip J. Stephens,Sarah Edkins,S. M. Clegg,Jon W. Teague,Hayley Woffendin,Mathew J. Garnett,William Bottomley,Neil Davis,Ed Dicks,Rebecca Ewing,Yvonne Floyd,Kristian Gray,S. Hall,Rachel Hawes,Jaime Hughes,Vivian Kosmidou,Andrew Menzies,Catherine Mould,Adrian Parker,Claire Stevens,Stephen Watt,Steven Hooper,Rebecca Wilson,Hiran Jayatilake,Barry A. Gusterson,Colin Cooper,Janet Shipley,Darren Hargrave,Kathy Pritchard-Jones,Norman J. Maitland,Georgia Chenevix-Trench,Gregory J. Riggins,Darell D. Bigner,Giuseppe Palmieri,Antonio Cossu,Adrienne M. Flanagan,Andrew G. Nicholson,Judy W. C. Ho,Suet Yi Leung,Siu Tsan Yuen,Barbara L. Weber,Hilliard F. Seigler,Timothy L. Darrow,Hugh Paterson,Richard Marais,Christopher J. Marshall,Richard Wooster,Michael R. Stratton,P. Andrew Futreal +51 more
TL;DR: BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers, with a single substitution (V599E) accounting for 80%.
Journal ArticleDOI
Lessons from Hereditary Colorectal Cancer
TL;DR: The authors are grateful to the members of their laboratories for their contributions to the reviewed studies and to F. Giardiello and S. Hamilton for photographs of colorectal lesions.
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Stabilization of β-Catenin by Genetic Defects in Melanoma Cell Lines
TL;DR: Genetic defects that result in up-regulation of β-catenin may play a role in melanoma progression.
Journal Article
Mutational Analysis of the APC/β-Catenin/Tcf Pathway in Colorectal Cancer
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Differential Regulation of Raf-1, A-Raf, and B-Raf by Oncogenic Ras and Tyrosine Kinases
TL;DR: Results show that maximal activation of B-Raf merely requires signals that generate Ras-GTP, whereas activation of Raf-1 and A-Rafa requires Ras- GTP together with signals that lead to their tyrosine phosphorylation, and B-raf may be the primary target of oncogenic Ras.
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Mutations of the BRAF gene in human cancer
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