B-Raf Is Dispensable for K-Ras-Mediated Oncogenesis in Human Cancer Cells

Kim, Jung-Sik; Lee, Carolyn; Foxworth, Aaron; Waldman, Todd

doi:10.1158/0008-5472.can-03-3862

Cited by 35 publications

(35 citation statements)

References 16 publications

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“…Given that the majority of colorectal cancers involve activation of the ␤-catenin signaling pathway, and given that multiple mutations lead to this activation, there is a clear need for drugs that attenuate the nuclear functions of ␤-catenin (15). Here, we report the discovery of a selective low molecular-weight inhibitor (ICG-001), which antagonizes ␤-catenin͞TCF-mediated transcription.…”

mentioning

confidence: 99%

A small molecule inhibitor of β-catenin/cyclic AMP response element-binding protein transcription

Emami

Nguyen

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

808

843

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Inherited and somatic mutations in the adenomatous polyposis coli occur in most colon cancers, leading to activation of β-catenin-responsive genes. To identify small molecule antagonists of this pathway, we challenged transformed colorectal cells with a secondary structure-templated chemical library, looking for compounds that inhibit a β-catenin-responsive reporter. We identified ICG-001, a small molecule that down-regulates β-catenin/T cell factor signaling by specifically binding to cyclic AMP response element-binding protein. ICG-001 selectively induces apoptosis in transformed cells but not in normal colon cells, reduces in vitro growth of colon carcinoma cells, and is efficacious in the Min mouse and nude mouse xenograft models of colon cancer.

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mentioning

confidence: 99%

A small molecule inhibitor of β-catenin/cyclic AMP response element-binding protein transcription

Emami

Nguyen

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

808

843

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“…In addition, constitutively active forms of Raf exhibit transforming activity comparable to Ras and are themselves sufficient to transform some cells. Interestingly, mutations of B-Raf and K-Ras are often found in the same tumor types, but in a mutually exclusive fashion, suggesting that B-Raf and KRas may provide an equivalent or at least a redundant oncogenic stimulus in cancer pathogenesis (31). Furthermore, dominant-negative mutants of Raf can impair Ras transforming activity, confirming that inhibition of Raf is a viable therapeutic approach.…”

Section: Ras-raf Signaling and Cancermentioning

confidence: 99%

Raf kinase as a target for anticancer therapeutics

Sridhar

Hedley

Siu

2005

Molecular Cancer Therapeutics

229

154

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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. [Mol Cancer Ther 2005;4(4):677 -85]

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“…This is due to mutation in either ␤-catenin itself or in negative regulators such as APC (17). The ␤-catenin⅐Tcf4 complex plays a central role in oncogenesis (18), and its inhibition by dominant negative Tcf4 stops proliferation of colorectal cancer cells and induces differentiation (19), proving that ␤-catenin is an important anti-cancer target (20). Recently, compounds inhibiting the association between ␤-catenin and Tcf4 have been described (7).…”

mentioning

confidence: 99%

Systematic Peptide Array-based Delineation of the Differential β-Catenin Interaction with Tcf4, E-Cadherin, and Adenomatous Polyposis Coli

Gail

Frank

Wittinghofer

2005

Journal of Biological Chemistry

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Nuclear accumulation of the complex between ␤-catenin and proteins of the T-cell factor (Tcf) family is a hallmark of many cancers. Targeting this interaction for drug development is complicated by the fact that Ecadherin and adenomatous polyposis coli (APC) bind to overlapping sites on ␤-catenin. Inhibiting their interactions might actually promote tumor growth. To identify selective ␤-catenin binding hot spots of Tcf4, E-cadherin, and APC, array technology with peptides of up to 53 amino acids length was used. Interactions were monitored by a quantitative fluorescent readout, which was shown to represent a monitor of true equilibrium binding constants. We identified minimal binding motifs in the ␤-catenin ligands and showed that most of the 15-mer and 20-mer repeats of APC did not interact, at least when non-phosphorylated, and defined a consensus binding motif also present in APC. We confirmed previously found hot spots and identified new ones. The method allowed us to locate a hydrophobic pocket that was relevant for the Tcf, but not the E-cadherin interaction, and would thus constitute an ideal drug target site.

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B-Raf Is Dispensable for K-Ras-Mediated Oncogenesis in Human Cancer Cells

Cited by 35 publications

References 16 publications

A small molecule inhibitor of β-catenin/cyclic AMP response element-binding protein transcription

A small molecule inhibitor of β-catenin/cyclic AMP response element-binding protein transcription

Raf kinase as a target for anticancer therapeutics

Systematic Peptide Array-based Delineation of the Differential β-Catenin Interaction with Tcf4, E-Cadherin, and Adenomatous Polyposis Coli

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