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Query: UNIPROT:P06889 (Mol)
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Anaplastic thyroid carcinoma (ATC) remains one of the most lethal human cancers. We hypothesized that sorafenib, a multikinase inhibitor of the BRaf, vascular endothelial growth factor receptor-2, and platelet-derived growth factor receptor-beta kinase, would decrease tumor growth and angiogenesis in an orthotopic model of ATC. The in vitro antiproliferative and proapoptotic effects of sorafenib on ATC cell lines were examined. To study the in vivo effects of sorafenib on orthotopic ATC tumors in nude mice, sorafenib was given p.o. at 40 or 80 mg/kg daily. Intratumoral effects were studied using immunohistochemical analysis. The effect of sorafenib on survival of the mice was also studied. Sorafenib inhibited the in vitro proliferation of ATC cell lines. Sorafenib also significantly inhibited tumor angiogenesis via the induction of endothelial apoptosis in an orthotopic model of thyroid cancer. As result, the growth of orthotopic ATC xenografts was reduced and the survival of the test animals was improved. Sorafenib exerts significant antitumor activity in an orthotopic xenograft model of ATC via a potent antiangiogenic effect. The antiangiogenic effects of sorafenib suggest that its use in clinical setting may not depend on the BRAF mutational status of thyroid tumors. Given the lack of curative options for patients with ATC, sorafenib warrants further study as a therapeutic agent against ATC.
Mol Cancer Ther 2007 Jun
PMID:Sorafenib inhibits the angiogenesis and growth of orthotopic anaplastic thyroid carcinoma xenografts in nude mice. 1757 7

The CpG island methylator phenotype (CIMP or CIMP-high) with extensive promoter methylation is a distinct phenotype in colorectal cancer. However, a choice of markers for CIMP has been controversial. A recent extensive investigation has selected five methylation markers (CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1) as surrogate markers for epigenomic aberrations in tumor. The use of these markers as a CIMP-specific panel needs to be validated by an independent, large dataset. Using MethyLight assays on 920 colorectal cancers from two large prospective cohort studies, we quantified DNA methylation in eight CIMP-specific markers [the above five plus CDKN2A (p16), CRABP1, and MLH1]. A CIMP-high cutoff was set at > or = 6/8 or > or = 5/8 methylated promoters, based on tumor distribution and BRAF/KRAS mutation frequencies. All but two very specific markers [MLH1 (98% specific) and SOCS1 (93% specific)] demonstrated > or = 85% sensitivity and > or = 80% specificity, indicating overall good concordance in methylation patterns and good performance of these markers. Based on sensitivity, specificity, and false positives and negatives, the eight markers were ranked in order as: RUNX3, CACNA1G, IGF2, MLH1, NEUROG1, CRABP1, SOCS1, and CDKN2A. In conclusion, a panel of markers including at least RUNX3, CACNA1G, IGF2, and MLH1 can serve as a sensitive and specific marker panel for CIMP-high.
J Mol Diagn 2007 Jul
PMID:Evaluation of markers for CpG island methylator phenotype (CIMP) in colorectal cancer by a large population-based sample. 1759 25

The aim of this study was to determine the frequency of microsatellite instability (MSI(+)) in tumors from a population-based series of young colorectal cancer patients and its correlation with the loss of expression of mismatch repair (MMR) proteins. The BAT-26 mononucleotide repeat was used to screen for MSI(+) in all colorectal cancers diagnosed in Western Australia throughout a 5-year period in patients <60 years of age. MSI(+) was found in 75 of 1003 (7.5%) cases, of which six contained a concomitant mutation in BRAF and were therefore excluded from further investigations as possible hereditary nonpolyposis colorectal cancer. Immunohistochemistry was used to evaluate expression of the four major MMR proteins (MLH1, MSH2, MSH6, and PMS2) in the remaining 69 MSI(+) tumors. Complete loss of MLH1 and PMS2 expression or of MSH2 and MSH6 expression was found in 35 (51%) and 17 (25%) cases, respectively, whereas other patterns of complete loss were observed in eight cases (12%). Eight tumors (12%) were initially recorded as showing normal expression, but on review seven were reclassified as having abnormal staining because of heterogeneous patterns of MMR loss. Three of these seven cases had previously been found to have germline mutations. Because of possible misinterpretation of heterogeneous immunohistochemistry staining for MMR protein loss, MSI testing is recommended as the initial screen for population-based detection of hereditary nonpolyposis colorectal cancer.
J Mol Diagn 2007 Sep
PMID:Heterogeneous staining for mismatch repair proteins during population-based prescreening for hereditary nonpolyposis colorectal cancer. 1827 72

Mutations in the BRAF gene are found in the majority of cutaneous malignant melanomas and subsets of other tumors. These mutations lead to constitutive activation of BRAF with increased downstream ERK (extracellular signal-regulated kinase) signaling; therefore, the development of RAF kinase inhibitors for targeted therapy is being actively pursued. A methodology that allows sensitive, cost-effective, high-throughput analysis of BRAF mutations will be needed to triage patients for specific molecular-based therapies. Pyrosequencing is a high-throughput, sequencing-by-synthesis method that is particularly useful for analysis of single nucleotide polymorphisms or hotspot mutations. Mutational analysis of BRAF is highly amenable to pyrosequencing because the majority of mutations in this gene localize to codons 600 and 601 and consist of single or dinucleotide substitutions. In this study, DNAs from a panel of melanocyte cell lines, melanoma cell lines, and melanoma tumors were used to validate a pyrosequencing assay to detect BRAF mutations. The assay demonstrates high accuracy and precision for detecting common and variant exon 15 BRAF mutations. Further, comparison of pyrosequencing data with 100K single nucleotide polymorphism microarray data allows characterization of BRAF amplification events that may accompany BRAF mutation. Pyro-sequencing serves as an excellent platform for BRAF genotyping of tumors from patients entering clinical trial.
J Mol Diagn 2007 Sep
PMID:Application of a BRAF pyrosequencing assay for mutation detection and copy number analysis in malignant melanoma. 1769 Feb 12

Constitutive activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) signaling pathway in human cancers is often associated with mutational activation of BRAF or RAS. MAPK/ERK kinase 1/2 kinases lie downstream of RAS and BRAF and are the only acknowledged activators of ERK1/2, making them attractive targets for therapeutic intervention. AZD6244 (ARRY-142886) is a potent, selective, and ATP-uncompetitive inhibitor of MAPK/ERK kinase 1/2. In vitro cell viability inhibition screening of a tumor cell line panel found that lines harboring BRAF or RAS mutations were more likely to be sensitive to AZD6244. The in vivo mechanisms by which AZD6244 inhibits tumor growth were investigated. Chronic dosing with 25 mg/kg AZD6244 bd resulted in suppression of growth of Colo-205, Calu-6, and SW-620 xenografts, whereas an acute dose resulted in significant inhibition of ERK1/2 phosphorylation. Increased cleaved caspase-3, a marker of apoptosis, was detected in Colo-205 and Calu-6 but not in SW-620 tumors where a significant decrease in cell proliferation was detected. Chronic dosing of AZD6244 induced a morphologic change in SW-620 tumors to a more differentiated phenotype. The potential of AZD6244 in combination with cytotoxic drugs was evaluated in mice bearing SW-620 xenografts. Treatment with tolerated doses of AZD6244 and either irinotecan or docetaxel resulted in significantly enhanced antitumor efficacy relative to that of either agent alone. These results indicate that AZD6244 has potential to inhibit proliferation and induce apoptosis and differentiation, but the response varies between different xenografts. Moreover, enhanced antitumor efficacy can be obtained by combining AZD6244 with the cytotoxic drugs irinotecan or docetaxel.
Mol Cancer Ther 2007 Aug
PMID:AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models. 1769 18

Mutational activation of Ras and a key downstream effector of Ras, the B-Raf serine/threonine kinase, has been observed in melanomas and colorectal carcinomas. These observations suggest that inhibition of B-Raf activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase kinase (MEK) and the extracellular signal-regulated kinase MAPK cascade may be an effective approach for the treatment of RAS and B-RAF mutation-positive melanomas and colon carcinomas. Although recent studies with interfering RNA (RNAi) and pharmacologic inhibitors support a critical role for B-Raf signaling in melanoma growth, whether mutant B-Raf has an equivalent role in promoting colorectal carcinoma growth has not been determined. In the present study, we used both RNAi and pharmacologic approaches to further assess the role of B-Raf activation in the growth of human melanomas and additionally determined if a similar role for mutant B-Raf is seen for colorectal carcinoma cell lines. We observed that RNAi suppression of mutant B-Raf(V600E) expression strongly suppressed the anchorage-dependent growth of B-RAF mutation-positive melanoma, but not colorectal carcinoma, cells. However, the anchorage-independent and tumorigenic growth of B-RAF mutation-positive colorectal carcinomas was dependent on mutant B-Raf function. Finally, pharmacologic inhibition of MEK and Raf was highly effective at inhibiting the growth of B-RAF mutation-positive melanomas and colorectal carcinoma cells, whereas inhibitors of other protein kinases activated by Ras (AKT, c-Jun NH(2)-terminal kinase, and p38 MAPK) were less effective. Our observations suggest that Raf and MEK inhibitors may be effective for the treatment of B-RAF mutation-positive colorectal carcinomas as well as melanomas.
Mol Cancer Ther 2007 Aug
PMID:Context-dependent roles of mutant B-Raf signaling in melanoma and colorectal carcinoma cell growth. 1769 19

Parathyroid hormone-related peptide (PTHrP) and the parathyroid hormone-PTHrP receptor increase chondrocyte proliferation and delay chondrocyte maturation in endochondral bone development at least partly through cyclic AMP (cAMP)-dependent signaling pathways. Because data suggest that the ability of cAMP to stimulate cell proliferation involves the mitogen-activated protein kinase kinase kinase B-Raf, we hypothesized that B-Raf might mediate the proliferative action of PTHrP in chondrocytes. Though B-Raf is expressed in proliferative chondrocytes, its conditional removal from cartilage did not affect chondrocyte proliferation and maturation or PTHrP-induced chondrocyte proliferation and PTHrP-delayed maturation. Similar results were obtained by conditionally removing B-Raf from osteoblasts. Because A-raf and B-raf are expressed similarly in cartilage, we speculated that they may fulfill redundant functions in this tissue. Surprisingly, mice with chondrocytes deficient in both A-Raf and B-Raf exhibited normal endochondral bone development. Activated extracellular signal-regulated kinase (ERK) was detected primarily in hypertrophic chondrocytes, where C-raf is expressed, and the suppression of ERK activation in these cells by PTHrP or a MEK inhibitor coincided with a delay in chondrocyte maturation. Taken together, these results demonstrate that B-Raf and A-Raf are dispensable for endochondral bone development and they indicate that the main role of ERK in cartilage is to stimulate not cell proliferation, but rather chondrocyte maturation.
Mol Cell Biol 2008 Jan
PMID:A-raf and B-raf are dispensable for normal endochondral bone development, and parathyroid hormone-related peptide suppresses extracellular signal-regulated kinase activation in hypertrophic chondrocytes. 1796 76

Thyroid cancer is the most common malignant tumor of the endocrine system and accounts for approximately 1% of all newly diagnosed cancer cases. The most frequent type of thyroid malignancy is papillary carcinoma, which constitutes approximately 80% of all cases. Papillary carcinomas frequently have genetic alterations leading to the activation of the MAPK signal pathway. Those include RET/PTC rearrangement and point mutations of the BRAF and RAS genes. Mutations in these genes are found in over 70% of papillary carcinomas and they rarely overlap in the same tumor. Frequent genetic alterations in follicular carcinomas, the second most common type of thyroid malignancy, include RAS mutations and PAX8-PPAR gamma rearrangement. RET point mutations are crucial for the development of medullary thyroid carcinomas. Many of these mutations, particularly those leading to the activation of the MAPK pathway, are being actively explored as therapeutic targets for thyroid cancer. Detection of these genetic alterations using molecular techniques is important for preoperative fine-needle aspiration diagnosis, prognosis and treatment of thyroid cancer.
Expert Rev Mol Diagn 2008 Jan
PMID:Molecular genetics of thyroid cancer: implications for diagnosis, treatment and prognosis. 1808 33

Mouse embryonic endothelial progenitor cells (eEPCs) acquire a mature phenotype after treatment with cyclic adenosine monophosphate (cAMP), suggesting an involvement of Raf serine/threonine kinases in the differentiation process. To test this idea, we investigated the role of B-Raf and C-Raf in proliferation and differentiation of eEPCs by expressing fusion proteins consisting of the kinase domains from Raf molecules and the hormone binding site of the estrogen receptor (ER), or its variant, the tamoxifen receptor. Our findings show that both B- and C-Raf kinase domains, when lacking adjacent regulatory parts, are equally effective in inducing eEPC differentiation. In contrast, the C-Raf kinase domain is a more potent stimulator of eEPC proliferation than B-Raf. In a complimentary approach, we used siRNA silencing to knockdown endogenously expressed B-Raf and C-Raf in eEPCs. In this experimental setting, we found that eEPCs lacking B-Raf failed to differentiate, whereas loss-of C-Raf function primarily slowed cell growth without impairing cAMP-induced differentiation. These findings were further corroborated in B-Raf null eEPCs, isolated from the corresponding knockout embryos, which failed to differentiate in vitro. Thus, gain- and loss-of-function experiments point to distinct roles of B-Raf and C-Raf in regulating growth and differentiation of endothelial progenitor cells, which may harbour therapeutic implications.
J Cell Mol Med
PMID:Rafs constitute a nodal point in the regulation of embryonic endothelial progenitor cell growth and differentiation. 1820 9

Na/H exchange regulatory factor 1 (NHERF1) is a scaffolding protein that regulates signaling and trafficking of several G protein-coupled receptors (GPCRs), including the parathyroid hormone receptor (PTH1R). GPCRs activate extracellular signal-regulated kinase (ERK)1/2 through different mechanisms. Here, we characterized NHERF1 regulation of PTH1R-stimulated ERK1/2. Parathyroid hormone (PTH) stimulated ERK1/2 phosphorylation by a protein kinase A (PKA)-dependent, but protein kinase C-, cyclic adenosine 5'-monophosphate-, and Rap1-independent pathway in Chinese hamster ovary cells stably transfected with the PTH1R and engineered to express NHERF1 under the control of tetracycline. NHERF1 blocked PTH-induced ERK1/2 phosphorylation downstream of PKA. This suggested that NHERF1 inhibitory effects on ERK1/2 occur at a postreceptor locus. Forskolin activated ERK1/2, and this effect was blocked by NHERF1. NHERF1 interacted with AKT and inhibited ERK1/2 activation by decreasing the stimulatory effect of 14-3-3 binding to B-Raf, while increasing the inhibitory influence of AKT negative regulation on ERK1/2 activation. This novel regulatory mechanism provides a new model by which cytoplasmic adapter proteins modulate ERK1/2 activation through a receptor-independent mechanism involving B-Raf.
Mol Biol Cell 2008 Apr
PMID:Na/H exchange regulatory factor 1, a novel AKT-associating protein, regulates extracellular signal-regulated kinase signaling through a B-Raf-mediated pathway. 1827 83


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