BRAF and K-ras gene mutations in human pancreatic cancers

Ishimura, Norihisa; Yamasawa, Kunihiro; Rumi, M.A. Karim; Kadowaki, Yasunori; Ishihara, Shunji; Amano, Yuji; Nio, Yoshinori; Higami, Tetsuya; Kinoshita, Yoshikazu

doi:10.1016/s0304-3835(03)00384-7

Cited by 64 publications

(52 citation statements)

References 8 publications

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“…Our report is consistent with the emerging evidence that while BRAF mutations are common in certain cancer types, such as colorectal and thyroid cancers and melanomas, they are rare to absent in many other malignancies, such as pancreatic, gastric, renal cell, and head and neck cancers. [26][27][28][29][30] In fact, even within one given cancer type, there exist dramatic differences in frequency of mutations based on tissue origin; thus while 80% of cutaneous melanomas harbor BRAF mutations, these are essentially absent in melanomas of the uveal tract. 19,31 The rarity (or absence) or BRAF mutations is biliary cancers implies that the V599E mutation is unlikely to be a useful biomarker for early detection of these cancers in bile fluids.…”

Section: Discussionmentioning

confidence: 99%

The V599E BRAF mutation is uncommon in biliary tract cancers

et al. 2004

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Activating point mutations of the BRAF oncogene have been identified in several solid tumors, most commonly in cutaneous melanomas and papillary carcinomas of the thyroid. A specific point mutation-V599E-accounts for the overwhelming majority of these mutational events. We explored the frequency of the V599E BRAF mutation in biliary tract cancers. In all, 62 archival biliary tract cancers, including 15 gallbladder cancers, 15 extrahepatic, and 10 intrahepatic cholangiocarcinomas from the United States, and 22 gallbladder carcinomas from Chile were analyzed for the V599E mutation of the BRAF gene using three distinct methods: direct sequencing, a primer extension method (Mutector s assay), and the highly sensitive quantitative Gap Ligase Chain Reaction. The common V599E mutation was not identified in any of the 62 biliary cancer samples using these three methods of detection. The V599E somatic mutation of the BRAF gene is absent in biliary tract cancers, at least in the two geographic populations (United States and Chile) examined. Activation of the RAS/ RAF/MAP kinase pathway in biliary tract cancers is likely to be secondary to oncogenic RAS mutations, or due to mutations of the BRAF gene at nucleotide positions not explored in the current study.

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Section: Discussionmentioning

confidence: 99%

The V599E BRAF mutation is uncommon in biliary tract cancers

et al. 2004

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“…11,12 Other cancers in which BRAF mutations have been described at a frequency >5% include ovarian cancer (low-grade serous tumors), cholangiocarcinoma, prostate cancer, and cisplatin-refractory germ cell tumors. [13][14][15][16] BRAF mutations have been observed in a small subset (<5%) of glioblastomas, nonsmall cell lung cancers, head and neck squamous cell cancers, breast cancers, and pancreatic cancers 1,6,[17][18][19] (Table 2). It is noteworthy that BRAF mutations are more common in certain clinical and pathologic subsets of melanoma, thyroid cancers, and colon cancers.…”

Section: Braf Biologymentioning

confidence: 99%

BRAF, a target in melanoma

Flaherty

McArthur

2010

Cancer

111

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The successful translation of therapies targeting signal-transduction pathways that are activated by oncogenes has provided a model for molecularly targeted therapy, and the identification of mutations in v-raf murine sarcoma viral oncogene homolog B1 (BRAF), a serine/threonine kinase, has turned the attention of the melanoma field toward this concept. The current review indicated that BRAF represents an important target in cancer, in part because it is present in 7% of all cancers and also because it represents the first intracellular signaling molecule that is activated by point mutations for which single-agent therapy appears to have efficacy. Therapy for advanced melanoma has progressed slowly over the past 3 decades, although significant advances have been made in other cancers with the application of cytotoxic chemotherapy and targeted therapies. However, in melanoma, cytotoxic chemotherapies have severe limits, chemotherapy does not convincingly improve on the natural history of metastatic disease and has no role in the adjuvant setting, and cytokine therapy may have a niche in both the adjuvant and metastatic settings but confers only a modest benefit to a small proportion of patients at the cost of severe toxicity. Thus, there are few other cancers in which completely novel therapies are so highly prioritized in clinical research. Understanding network of signal-transduction pathways and how that network may adapt to BRAF inhibition or mitogen-activated protein kinase kinase inhibition will point to the next generation of clinical trials investigating rational combination regimens. The current investigations in melanoma will create a set of hypotheses to be tested in each cancer that harbors BRAF mutations. Cancer 2010;116:4902-13. V C 2010 American Cancer Society.KEYWORDS: BRAF, melanoma, oncogene, kinase inhibitor, mutation.Therapy for advanced melanoma has progressed slowly over the past 3 decades, whereas significant advances have been made with the application of cytotoxic chemotherapy and, more recently, targeted therapies in other cancers. The application of cytotoxic chemotherapies that have disease-altering ability in other cancers has severe limits in melanoma. Chemotherapy does not convincingly improve upon the natural history of metastatic disease and has no role in the adjuvant setting. Cytokine therapy has a niche in both the adjuvant and metastatic settings but confers a modest benefit to a small proportion of patients at the cost of severe toxicity. Thus, there are few other cancers in which completely novel therapies are so highly prioritized in clinical research. The successful translation of therapies targeting signal-transduction pathways that are activated by oncogenes has provided a model for molecularly targeted therapy. The identification of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations in 2002 was the watershed event that turned the attention of the melanoma field to this concept. 1 BRAF BiologyRaf kinases are components of the mitogen-activated protein (MAP) k...

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“…Because activating Raf mutations occur rarely in pancreatic cancer (6,30,31), we first determined by Western blotting whether B-Raf and other Raf isoforms are activated in human pancreatic cancer cell lines. Moreover, as the tumor microenvironment also consists of tumor endothelial cells and pericytes that eventually could be affected by antiRaf targeted therapy, the expression and activation of Raf kinase isoforms was additionally determined in these cell types.…”

Section: Effects Of Raf Inhibition On Signaling Pathway Activation Inmentioning

confidence: 99%

Dual targeting of Raf and VEGF receptor 2 reduces growth and metastasis of pancreatic cancer through direct effects on tumor cells, endothelial cells, and pericytes

Lang¹,

Schachtschneider²,

Moser³

et al. 2008

Molecular Cancer Therapeutics

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The Ras/Raf/MEK pathway represents an important oncogenic signaling pathway in gastrointestinal malignancies, including pancreatic cancer. Although activating B-Raf mutations are infrequent in pancreatic cancer, we hypothesized that targeting Raf could be valuable for therapy of this cancer entity. Moreover, as vascular endothelial growth factor receptor 2 (VEGFR2) is involved in tumor angiogenesis, we sought to investigate the effects of dual inhibition of Raf and VEGFR2 on pancreatic tumor growth, vascularization, and metastasis. Effects of a Raf/VEGFR2 inhibitor (NVP-AAL881) on pancreatic cancer cells, endothelial cells, and vascular smooth muscle cells were determined by Western blotting, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis, and migration assays, respectively. Changes in the expression of VEGF-A or survivin were investigated by ELISA and/or real-time PCR. The growthinhibitory effects of Raf/VEGFR2 inhibition were additionally evaluated in orthotopic tumor models. Results showed that various Raf isoforms were activated in pancreatic cancer cells and NVP-AAL881 diminished the activation of MEK, Akt, Erk, and also STAT3. Moreover, dual inhibition of Raf/VEGFR2 significantly reduced VEGF expression and impaired cancer cell migration. Importantly, besides blocking VEGF-induced Erk and SAPK phosphorylation in endothelial cells, the Raf inhibitor diminished STAT3 phosphorylation, independent of a VEGFR2 blockade, and reduced the expression of survivin. In addition, cell proliferation and migration of both endothelial cells and vascular smooth muscle cells were significantly reduced. In vivo, blocking Raf/VEGFR2 significantly inhibited orthotopic tumor growth and vascularization and reduced cancer metastasis. In conclusion, blocking Raf exerts growth-inhibitory effects on pancreatic tumor cells, endothelial cells, and pericytes and elicits antiangiogenic properties. Dual targeting of Raf and VEGFR2 appears to be a valid strategy for therapy of pancreatic cancer.

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BRAF and K-ras gene mutations in human pancreatic cancers

Cited by 64 publications

References 8 publications

The V599E BRAF mutation is uncommon in biliary tract cancers

The V599E BRAF mutation is uncommon in biliary tract cancers

BRAF, a target in melanoma

Dual targeting of Raf and VEGF receptor 2 reduces growth and metastasis of pancreatic cancer through direct effects on tumor cells, endothelial cells, and pericytes

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