New insight into BRAF mutations in cancer

Dhomen, Nathalie; Marais, Richard

doi:10.1016/j.gde.2006.12.005

Cited by 244 publications

(200 citation statements)

References 66 publications

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“…We found that colorectal cancer cell lines were also highly susceptible to IGFBP7-mediated apoptosis, consistent with the high frequency of activating BRAF or RAS mutations, and presumably increased BRAF-MEK-ERK signaling, in colorectal cancers (1,9). Significantly, previous studies have found that IGFBP7 expression is lost in human colorectal cancers (17,18), consistent with the possibility that IGFBP7 is a colorectal cancer tumor suppressor (19,20).…”

Section: Discussionsupporting

confidence: 86%

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Efficacy of IGFBP7 for treatment of metastatic melanoma and other cancers in mouse models and human cell lines

Wajapeyee

Kapoor

Mahalingam

et al. 2009

Molecular Cancer Therapeutics

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We recently identified the secreted protein IGFBP7 as a factor required for an activated BRAF oncogene to induce senescence or apoptosis in primary human cells. In human melanomas containing an activating BRAF mutation (BRAF-positive melanomas), IGFBP7 is epigenetically silenced, which seems to be a critical step in melanoma genesis. Restoration of IGFBP7 function by the addition of recombinant IGFBP7 (rIGFBP7) induces apoptosis in BRAF-positive human melanoma cell lines, and systemically administered rIGFBP7 markedly suppresses the growth of BRAF-positive primary tumors in xenografted mice. Here we further evaluate the role of IGFBP7 in the treatment of BRAF-positive melanoma and other malignancies. We find that in human metastatic melanoma samples IGFBP7 is epigenetically silenced and at an even higher frequency than that found in primary melanomas. Using a murine experimental metastasis assay, we show that systemic administration of rIGFBP7 markedly suppresses the growth of metastatic disease and prolongs survival. An analysis of the NCI60 panel of human cancer cell lines reveals that in addition to melanoma, IGFBP7 induces apoptosis in several other cancer types, in particular colorectal cancer cell lines. In general, IGFBP7 induces apoptosis in human cancer cell lines that have an activating mutation in BRAF or RAS, and that are sensitive to chemical inhibition of BRAF-MEK-ERK signaling. Significantly, systemically administered rIGFBP7 blocks the growth of colorectal tumors containing an activating RAS or BRAF mutation in mouse xenografts. The results presented here, in conjunction with those from previous studies, justify the further development of IGFBP7 as an anticancer agent.

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Section: Discussionsupporting

confidence: 86%

“…1). RAF activates the MAP kinase extracellular signal-regulated kinase (MEK), which in turn phosphorylates and activates extracellular signal-regulated kinases 1 (ERK1) and 2 (ERK2).…”

Section: Introductionmentioning

confidence: 99%

Efficacy of IGFBP7 for treatment of metastatic melanoma and other cancers in mouse models and human cell lines

Wajapeyee

Kapoor

Mahalingam

et al. 2009

Molecular Cancer Therapeutics

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“…Recent data suggest that the roles of the three RAF isoforms, ARAF (A-Raf), BRAF, and CRAF, are more complex than initially thought (20). BRAF and CRAF are widely expressed and expressed together in most cells, whereas ARAF expression is restricted mainly to germ cells (21).…”

Section: Discussionmentioning

confidence: 99%

Mutation that blocks ATP binding creates a pseudokinase stabilizing the scaffolding function of kinase suppressor of Ras, CRAF and BRAF

Yu²,

Kornev

et al. 2011

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

116

175

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Because mutations in RAS and BRAF represent the most common mutations found in human tumors, identification of inhibitors has been a major goal. Surprisingly, new oncogenic BRAF specific inhibitors inhibit cells transformed with mutated BRAF but paradoxically stimulate the growth of cells transformed with RAS. Here, we show that the mechanism for activation is via drug-induced dimer formation between CRAF and kinase suppressor of Ras (KSR)1. To understand the function of KSR1, we generated a KSR1 mutant that cannot bind ATP but stabilizes the closed, active conformation of KSR1. Molecular modeling suggested that the mutant stabilizes the two hydrophobic spines critical for the closed active conformation. We, therefore, could use the mutant to discriminate between the scaffold versus kinase functions of KSR1. The KSR1 mutant bound constitutively to RAF and mitogen-activated protein kinase kinase (MEK) but could not reconstitute activity suggesting that the catalytic activity of KSR1 is required for its function. Analogous mutations in BRAF and CRAF allowed us to test the generality of the model. The mutation induced changes consistent with the active, closed conformation of both kinases and confirmed that BRAF functions distinctly from CRAF in the MAP kinase pathway. Not only does this work suggest that KSR1 may function as a kinase, we anticipate that the mutation that we generated may be broadly applicable to stabilize the closed conformation of other kinases many of which may also form dimers.cancer | protein kinase | signal transduction

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“…This mutation induces constitutive activation of mitogen-activated protein kinase (MAPK) signaling, and is associated with uncontrolled cell growth, proliferation, and tumorigenesis (Gray-Schopfer et al 2005, Xing 2005, Dhomen & Marais 2007. Several studies found that mutation of BRAF was associated with cancer cell sensitivity to a BRAF/MEK blockade (Dignam et al 1983, Cohen et al 2003, Ball et al 2007, Liu et al 2007, Liu & Xing 2008, but the detailed mechanisms are not well understood.…”

Section: Introductionmentioning

confidence: 99%

The influence of the BRAF V600E mutation in thyroid cancer cell lines on the anticancer effects of 5-aminoimidazole-4-carboxamide-ribonucleoside

Choi

Kim

Chung³

et al. 2011

Journal of Endocrinology

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5-Aminoimidazole-4-carboxamide-ribonucleoside (AICAR) is an activator of 50 -AMP-activated protein kinase (AMPK), which plays a role in the maintenance of cellular energy homeostasis. Activated AMPK inhibits the protein kinase mechanistic target of rapamycin, thereby reducing the extent of protein translation and suppressing both cell growth and cell cycle entry. Recent reports indicate that AMPKmediated growth inhibition is achieved via an action of the RAF-MEK-ERK mitogen-activated protein kinase pathway in melanoma cells harboring the V600E mutant form of the BRAF oncogene. In this study, we investigated the anticancer efficacy of AICAR by measuring its effects on proliferation, apoptosis, and cell cycle progression of BRAF wild-type and V600E-mutant thyroid cancer cell lines. We also explored the mechanism underlying these effects.AICAR inhibited the proliferation of BRAF V600E-mutant thyroid cancer cell lines more strongly than was the case with wild-type cell lines. The suppressive effect of AICAR on cell proliferation was associated with increased S-phase cell cycle arrest and apoptosis. Interestingly, AICAR suppressed phosphorylation of ERK and p70S6K in BRAF V600E-mutant thyroid cancer cells, but rather increased phosphorylation in wild-type cells. Together, the results indicate that AICAR-induced AMPK activation in BRAF V600E-mutant thyroid cancer cell lines resulted in increases in apoptosis and S-phase arrest via downregulation of ERK and p70S6K activity. Thus, regulation of AMPK activity may be potentially useful as a therapy for thyroid cancer if the cancer harbors a BRAF V600E mutation.

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New insight into BRAF mutations in cancer

Cited by 244 publications

References 66 publications

Efficacy of IGFBP7 for treatment of metastatic melanoma and other cancers in mouse models and human cell lines

Efficacy of IGFBP7 for treatment of metastatic melanoma and other cancers in mouse models and human cell lines

Mutation that blocks ATP binding creates a pseudokinase stabilizing the scaffolding function of kinase suppressor of Ras, CRAF and BRAF

The influence of the BRAF V600E mutation in thyroid cancer cell lines on the anticancer effects of 5-aminoimidazole-4-carboxamide-ribonucleoside

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