Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activating mutations in KRAS and BRAF are found in more than 30% of all human tumours and 40% of melanoma, respectively, thus targeting this pathway could have broad therapeutic effects. Small molecule ATP-competitive RAF kinase inhibitors have potent antitumour effects on mutant BRAF(V600E) tumours but, in contrast to mitogen-activated protein kinase kinase (MEK) inhibitors, are not potent against RAS mutant tumour models, despite RAF functioning as a key effector downstream of RAS and upstream of MEK. Here we show that ATP-competitive RAF inhibitors have two opposing mechanisms of action depending on the cellular context. In BRAF(V600E) tumours, RAF inhibitors effectively block the mitogen-activated protein kinase (MAPK) signalling pathway and decrease tumour growth. Notably, in KRAS mutant and RAS/RAF wild-type tumours, RAF inhibitors activate the RAF-MEK-ERK pathway in a RAS-dependent manner, thus enhancing tumour growth in some xenograft models. Inhibitor binding activates wild-type RAF isoforms by inducing dimerization, membrane localization and interaction with RAS-GTP. These events occur independently of kinase inhibition and are, instead, linked to direct conformational effects of inhibitors on the RAF kinase domain. On the basis of these findings, we demonstrate that ATP-competitive kinase inhibitors can have opposing functions as inhibitors or activators of signalling pathways, depending on the cellular context. Furthermore, this work provides new insights into the therapeutic use of ATP-competitive RAF inhibitors.
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PMID:RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. 2023 52

The synthesis of a novel series of pyrimidin-4-yl-1H-imidazol-2-yl derivatives 7, 8, 9 and their antiproliferative activities against A375P human melanoma cell line and WM3629 cell line were described. Most compounds showed superior antiproliferative activities compared to Sorafenib, the well-known RAF inhibitor. Among them, 7a exhibited potent activities on both cell lines (IC(50)=0.62 and 4.49muM, respectively) and turned out to be a selective and potent CRAF inhibitor.
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PMID:Discovery and initial SAR of pyrimidin-4-yl-1H-imidazole derivatives with antiproliferative activity against melanoma cell lines. 2014 58

We describe the design, synthesis, and optimization of a series of new inhibitors of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF), a kinase whose mutant form (V600E) is implicated in several types of cancer, with a particularly high frequency in melanoma. Our previously described inhibitors with a tripartite A-B-C system (where A is a hinge binding pyrido[4,5-b]imidazolone system, B is an aryl spacer group, and C is a heteroaromatic group) were potent against purified (V600E)BRAF in vitro but were less potent in accompanying cellular assays. Substitution of different aromatic heterocycles for the phenyl based C-ring is evaluated herein as a potential means of improving the cellular potencies of these inhibitors. Substituted pyrazoles, particularly 3-tert-butyl-1-aryl-1H-pyrazoles, increase the cellular potencies without detrimental effects on the potency on isolated (V600E)BRAF. Thus, compounds have been synthesized that inhibit, with low nanomolar concentrations, (V600E)BRAF, its downstream signaling in cells [as measured by the reduction of the phosphorylation of extracellular regulated kinase (ERK)], and the proliferation of mutant BRAF-dependent cells. Concomitant benefits are good oral bioavailability and high plasma concentrations in vivo.
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PMID:Development of novel, highly potent inhibitors of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF): increasing cellular potency through optimization of a distal heteroaromatic group. 2019 87

Cultured human melanocytes are increasingly being used in the treatment of vitiligo. The growth media contain various types of mitogenic factors, both recombinant human (e.g., rhbFGF and rhSCF) and synthetic (e.g., TPA). High concentrations of mitogenic factors accelerate the cell cycle, and consequently may increase the risk of carcinogenesis of transplanted cells. Mutations of genes of the RAS/RAF/MEK/ERK signaling pathway are very often found in the early stages of the development of melanoma. TPA is considered to be an oncogenic factor, but so far there is no evidence to show that it is responsible for damage to the genetic material of cultured melanocytes. The aim of our study was to assess the risk of the development of mutations in selected genes of the RAS/RAF/MEK/ERK signaling pathway during the culturing of melanocytes in various growth media. Based on the results obtained, it can be concluded that TPA and high concentrations of other growth factors intensify the proliferation of melanocytes, without the risk of damage to the HRAS (exon 1 and 2), KRAS (exon 1 and 2), NRAS (exon 1 and 2), and BRAF (exon 11 and 15) genes. In order to assess the total safety of the transplantation of cultured melanocytes, it is necessary to carry out further studies on other signaling pathways as well as carry out biological tests on an animal model.
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PMID:Transplantation of cultured autologous melanocytes: hope or danger? 2035 Mar 53

BRAF is a member of the RAF kinase family, which acts in the ERK/MAP kinase pathway, a signalling cascade that regulates cellular proliferation, differentiation and survival. Single point mutations can turn BRAF into an oncogene, but there appears to be a cell type/tumour specific relevance for BRAF kinase-activating mutations, since they are found predominantly in cutaneous melanoma. With the success of targeting other oncogenic kinases such as BCR-ABL, KIT or members of the epidermal-growth factor receptor (EGFR) family in other cancers, the expectations were high when the first RAF kinase-targeting drug (sorafenib) reached clinical trials. However, disappointingly the first studies using sorafenib in melanoma patients did not show the anticipated single agent efficacy. More recently, the resolution of the BRAF crystal structure has led to the development of better, more specific BRAF inhibitors such as the Plexxikon compound, PLX4032, which induced a dramatic response rate in phase I trials, validating BRAF as a clinically relevant target. In addition, our understanding of melanoma biology and the role BRAF is playing therein has improved significantly. The complexity in the ERK/MAP kinase pathway including important feedback mechanisms has been dissected, and the relevance of cross-talks with other signalling pathways has been revealed, suggesting strategies for the design of improved, more efficient combinatorial therapies. This review highlights the relevance of BRAF and the ERK/MAP kinase pathway for melanoma cell biology and discusses some of the recent advances in both, the understanding of BRAF function in melanoma and the development of improved BRAF targeting inhibitors.
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PMID:BRAF as therapeutic target in melanoma. 2035 May 35

The Mitogen Activated Protein Kinase (MAPK) pathway plays a key role in melanoma development making it an important therapeutic target. In normal cells, the tightly regulated pathway relays extracellular signals from cell membrane to nucleus via a cascade of phosphorylation events. In melanomas, dysregulation of the MAPK pathway occurs frequently due to activating mutations in the B-RAF and RAS genes or other genetic or epigenetic modifications, leading to increased signaling activity promoting cell proliferation, invasion, metastasis, migration, survival and angiogenesis. However, identification of ideal pathway member to therapeutically target for maximal clinical benefit to melanoma patients remains a challenge. This review provides an overview of the obstacles faced targeting the MAPK pathway and why certain therapeutic approaches succeed while others fail. The review summarizes the roles played by the proteins, therapeutic potential and the drugs available to target each member of the pathway as well as concerns related to each. Potential for targeting multiple points and inhibiting other pathways along with MAPK inhibition for optimal efficacy are discussed along with explanations for development of drug resistance, which includes discussions related to cross-talk between pathways, RAF kinase isoform switching and phosphatase deregulation. Finally, the use of nanotechnology is reviewed as an approach to target the MAPK pathway using both genetic and pharmacological agents simultaneously targeting multiple points in the pathway or in combination with other cascades.
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PMID:Targeting the MAPK pathway in melanoma: why some approaches succeed and other fail. 2045 Aug 91

Melanoma remains notoriously resistant to current chemotherapeutics, leaving an acute need for novel therapeutic approaches. The aim of this study was to determine the prognostic and therapeutic significance of X-linked inhibitor of apoptosis protein (XIAP) in melanoma through correlation of XIAP expression with disease stage, RAS/RAF mutational status, clinical outcome, and susceptibility to endoplasmic reticulum (ER) stress-induced cell death. XIAP expression and N-RAS/B-RAF mutational status were retrospectively determined in a cohort of 55 primary cutaneous melanocytic lesions selected and grouped according to the American Joint Committee on Cancer staging system. Short hairpin RNA interference of XIAP was used to analyze the effect of XIAP expression on ER stress-induced apoptosis in response to fenretinide or bortezomib in vitro. The results showed that XIAP positivity increased with progressive disease stage, although there was no significant correlation between XIAP positivity and combined N-RAS/B-RAF mutational status or clinical outcome. However, XIAP knockdown significantly increased ER stress-induced apoptosis of melanoma cells in a caspase-dependant manner. The correlation of XIAP expression with disease stage, as well as data showing that XIAP knockdown significantly increases fenretinide and bortezomib-induced apoptosis of metastatic melanoma cells, suggests that XIAP may prove to be an effective therapeutic target for melanoma therapy.
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PMID:Targeting X-linked inhibitor of apoptosis protein to increase the efficacy of endoplasmic reticulum stress-induced apoptosis for melanoma therapy. 2106 53

Although recurrent gene fusions involving erythroblastosis virus E26 transformation-specific (ETS) family transcription factors are common in prostate cancer, their products are considered 'undruggable' by conventional approaches. Recently, rare targetable gene fusions involving the anaplastic lymphoma receptor tyrosine kinase (ALK) gene, have been identified in 1-5% of lung cancers, suggesting that similar rare gene fusions may occur in other common epithelial cancers, including prostate cancer. Here we used paired-end transcriptome sequencing to screen ETS rearrangement-negative prostate cancers for targetable gene fusions and identified the SLC45A3-BRAF (solute carrier family 45, member 3-v-raf murine sarcoma viral oncogene homolog B1) and ESRP1-RAF1 (epithelial splicing regulatory protein-1-v-raf-1 murine leukemia viral oncogene homolog-1) gene fusions. Expression of SLC45A3-BRAF or ESRP1-RAF1 in prostate cells induced a neoplastic phenotype that was sensitive to RAF and mitogen-activated protein kinase kinase (MAP2K1) inhibitors. Screening a large cohort of patients, we found that, although rare, recurrent rearrangements in the RAF pathway tend to occur in advanced prostate cancers, gastric cancers and melanoma. Taken together, our results emphasize the key role of RAF family gene rearrangements in cancer, suggest that RAF and MEK inhibitors may be useful in a subset of gene fusion-harboring solid tumors and demonstrate that sequencing of tumor transcriptomes and genomes may lead to the identification of rare targetable fusions across cancer types.
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PMID:Rearrangements of the RAF kinase pathway in prostate cancer, gastric cancer and melanoma. 2083 79

In a series of articles published in February 2010, The New York Times chronicled, from a personal perspective, the rollercoaster experience of those associated with clinical trials of a RAF inhibitor for the treatment of melanoma. In this issue of Science Translational Medicine, Whittaker et al. describe research that reconciles some of the bewildering aspects of the discovery and development of drugs that inhibit such protein kinase targets in cancer.
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PMID:On or off target: mutations, models, and predictions. 2053 18

V-RAF murine sarcoma viral oncogene homolog B1 (BRAF) is a serine/threonine-specific protein kinase that is mutated with high frequency in cutaneous melanoma, and many other cancers. Inhibition of mutant BRAF is an attractive therapeutic approach for the treatment of melanoma. A triarylimidazole BRAF inhibitor bearing a phenylpyrazole group (dimethyl-[2-(4-{5-[4-(1H-pyrazol-3-yl)-phenyl]-4-pyridin-4-yl-1H-imidazol-2-yl}-phenoxy)-ethyl]-amine, 1a) was identified as an active BRAF inhibitor. Based on this starting point, we synthesized a series of analogues leading to the discovery of 6-{2-[4-(4-methyl-piperazin-1-yl)-phenyl]-5-pyridin-4-yl-3H-imidazol-4-yl}-2,4-dihydro-indeno[1,2-c]pyrazole (1j), with nanomolar activity in three assays: inhibition of purified mutant BRAF activity in vitro; inhibition of oncogenic BRAF-driven extracellular regulated kinase (ERK) activation in BRAF mutant melanoma cell lines; and inhibition of proliferation in these cells.
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PMID:Novel tricyclic pyrazole BRAF inhibitors with imidazole or furan central scaffolds. 2066 40


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