RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF

Poulikakos, Poulikos I.; Zhang, Chao; Bollag, Gideon; Shokat, Kevan M.; Rosen, Neal

doi:10.1038/nature08902

Cited by 1,637 publications

(1,671 citation statements)

References 24 publications

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“…19 This mechanism might have clinical implications because promoted dimerization of CRAF and BRAF could lead to resistance to RAF inhibitors. 20,21 In this study, we report a novel complex BRAF mutation, BRAF V600delinsYM , identified in 4 out of 492 Japanese PTC cases (0.81%). We also performed its functional characterization, and it showed constitutively active kinase function and transforming ability, suggesting that it is a new PTC oncogene that activates the MAPK signaling pathway as does BRAF V600E .…”

mentioning

confidence: 78%

Functional characterization of the novel BRAF complex mutation, BRAF^V600delinsYM, identified in papillary thyroid carcinoma

Matsuse

Mitsutake

Tanimura

et al. 2012

Intl Journal of Cancer

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An activating mutation in the BRAF gene is the most common genetic alteration in papillary thyroid carcinomas (PTCs). The mutation in PTCs is almost a c.1799T>A transversion, resulting in a p.V600E amino acid substitution (BRAFV600E). Here, we report a novel complex BRAF mutation identified in 4/492 Japanese PTC cases (0.81%). The mutation was comprised of one nucleotide substitution at position 1798, followed by an in‐frame insertion of three nucleotides, c.1798delinsTACA in Exon 15, resulting in p.V600delinsYM. In silico three‐dimensional protein structure prediction implied altered kinase activity of this mutant. In vitro kinase assay and western blotting revealed that this mutation conferred high kinase activity on the BRAF protein, leading to constitutive activation of the MAPK signaling pathway. The mutation also showed high transforming ability in focus formation assay using NIH3T3 cells. The degree of all the functional characteristics was comparable to that of BRAFV600E, and treatment with a BRAF inhibitor Sorafenib was also equally effective in this mutant. These findings suggest that the novel BRAF mutation, BRAFV600delinsYM, is a gain‐of‐function mutation and plays an important role in PTC development.

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mentioning

confidence: 78%

Functional characterization of the novel BRAF complex mutation, BRAF^V600delinsYM, identified in papillary thyroid carcinoma

Matsuse

Mitsutake

Tanimura

et al. 2012

Intl Journal of Cancer

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“…This work was essential in identifying MEK as being of particular importance in BRAF-inhibitor resistance and, thus, the potential synergy between BRAF and MEK inhibitors 55 . The mechanistic specificity of this work additionally led to the description of a phenomenon dubbed 'paradoxical activation' of the MAPK pathway via BRAF inhibition in BRAF-wild-type cells, for example, keratinocytes [56][57][58][59] . This discovery suggested that some of the hyperproliferative cutaneous manifestations associated with BRAF inhibition in the clinic might be mitigated by combination therapy incorporating a MEK inhibitor.…”

Section: Braf-targeted Therapiesmentioning

confidence: 99%

Targeted agents and immunotherapies: optimizing outcomes in melanoma

et al. 2017

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“…Thus, the effective and global coverage of metastatic cells represents a critical factor for optimizing therapeutic outcome. Although novel targeted therapies such as BRAF inhibitors (Yang et al, 2010) and anti-CTLA4 antibodies (Camacho et al, 2009) are showing promising results in melanoma clinical trials, resistance to these compounds and patient relapse are rapidly emerging (Poulikakos et al, 2010). Small interfering RNA-mediated therapies, such as targeting BCL2 with the antisense oligonucleotide Oblimersen (Jansen et al, 2000), also had limited success.…”

Section: Introductionmentioning

confidence: 99%

Efficient in vivo microRNA targeting of liver metastasis

et al. 2010

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Targeting oncogenic microRNAs (miRNAs) is emerging as a promising strategy for cancer therapy. In this study, we provide proof of principle for the safety and efficacy of miRNA targeting against metastatic tumors. We tested the impact of targeting miR-182, a pro-metastatic miRNA frequently overexpressed in melanoma, the in vitro silencing of which represses invasion and induces apoptosis. Specifically, we assessed the effect of anti-miR-182 oligonucleotides synthesized with 2 0 sugar modifications and a phosphorothioate backbone in a mouse model of melanoma liver metastasis. Luciferase imaging showed that mice treated with anti-miR-182 had a lower burden of liver metastases compared with control. We confirmed that miR-182 levels were effectively downregulated in the tumors of anti-miR-treated mice compared with tumors of control-treated mice, both in the liver and in the spleen. This effect was accompanied by an upregulation of multiple miR-182 direct targets. Transcriptional profiling of tumors treated with anti-miR-182 or with control oligonucleotides revealed an enrichment of genes controlling survival, adhesion and migration modulated in response to anti-miR-182 treatment. These data indicate that in vivo administration of anti-miRs allows for efficient miRNA targeting and concomitant upregulation of miRNAcontrolled genes. Our results demonstrate that the use of anti-miR-182 is a promising therapeutic strategy for metastatic melanoma and provide a solid basis for testing similar strategies in human metastatic tumors.

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RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF

Cited by 1,637 publications

References 24 publications

Functional characterization of the novel BRAF complex mutation, BRAF^V600delinsYM, identified in papillary thyroid carcinoma

Functional characterization of the novel BRAF complex mutation, BRAF^V600delinsYM, identified in papillary thyroid carcinoma

Targeted agents and immunotherapies: optimizing outcomes in melanoma

Efficient in vivo microRNA targeting of liver metastasis

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RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF

Cited by 1,637 publications

References 24 publications

Functional characterization of the novel BRAF complex mutation, BRAFV600delinsYM, identified in papillary thyroid carcinoma

Functional characterization of the novel BRAF complex mutation, BRAFV600delinsYM, identified in papillary thyroid carcinoma

Targeted agents and immunotherapies: optimizing outcomes in melanoma

Efficient in vivo microRNA targeting of liver metastasis

Contact Info

Product

Resources

About

Functional characterization of the novel BRAF complex mutation, BRAF^V600delinsYM, identified in papillary thyroid carcinoma

Functional characterization of the novel BRAF complex mutation, BRAF^V600delinsYM, identified in papillary thyroid carcinoma