Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activating mutations in the BRAF kinase have been reported in a large number of cases of malignant melanoma. This suggests that therapy with specific RAF kinase inhibitors may find use in treating this disease. If the response to RAF kinase inhibition is dependent on the presence of an activated BRAF protein, it will be necessary to evaluate cases of malignant melanoma for the presence or absence of BRAF mutations. High-resolution amplicon melting analysis is able to detect single base-pair changes in DNA isolated from paraffin-embedded tissue sections and obviates the need for direct DNA sequencing. Results can be available within 48 hours. In this report, we used high-resolution amplicon melting analysis to evaluate 90 cases of malignant melanoma for BRAF mutations. Of these 90 cases, 74 were metastatic melanomas, 12 were primary cutaneous melanomas, and 4 were in situ melanomas. BRAF activation mutations were found in 43 cases (48%). Forty-one of these mutations were in exon 15. The mutations in exon 15 included V600E (34 cases), V600K (6 cases), and V600R (1 case). Two activating mutations were found in exon 11, G469V and G469R. The presence or absence of a BRAF mutation in the junctional component of an invasive melanoma was maintained in the invasive component. We also evaluated these 90 cases, as well as an additional 10 cases (total of 100) for the expression of c-kit. The majority of invasive and metastatic malignant melanomas did not express c-kit, although all in situ lesions and the junctional components of invasive lesions were strongly c-kit positive. Surprisingly, 2 cases of metastatic malignant melanoma (2%) showed strong and diffuse c-kit expression and contained a c-kit-activating mutation, L576P, as detected by high-resolution amplicon melting analysis and confirmed by direct DNA sequencing. These 2 c-kit mutation-positive cases did not contain BRAF mutations. The presence of a c-kit-activating mutation in metastatic malignant melanoma suggests that a small number of melanomas may progress by a somatic mutation of the c-kit gene. The presence of BRAF- and c-kit-activating mutations in malignant melanoma suggests new approaches to treating this disease involving specific tyrosine kinase inhibitors may prove worthwhile and that mutation analysis by high-resolution melting analysis might help guide therapy.
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PMID:Human malignant melanoma: detection of BRAF- and c-kit-activating mutations by high-resolution amplicon melting analysis. 1594 15

Gliosarcomas are rare and poorly characterized malignant brain tumors that exhibit a biphasic tissue pattern with areas of gliomatous and sarcomatous differentiation. These tumors are histological variants of glioblastoma, displaying a similar genetic profile and dismal prognosis. Up-regulation of PDGFR subfamily of tyrosine kinase members, PDGFR-alpha and c-Kit, and their intracellular effectors RAS/RAF/MAPK has a crucial role in the cancer development. In addition, signal transduction mediated by activating mutations of c-Kit and PDGFR can be effectively blocked by specific tyrosine kinase inhibitors, such as Imatinib mesylate. The aim of this study was to characterize the molecular alterations of PDGFR signaling in gliosarcomas. Six cases were analyzed by immunohistochemistry for the expression of PDGFR-alpha, c-Kit and their ligands PDGF-A and SCF, respectively. The cases were further evaluated for the presence of activating mutations of PDGFR-alpha (exons 12 and 18) and c-kit (exons 9, 11, 13, and 17), as well as B-RAF (exons 11 and 15). Expression of PDGF-A was found in all cases and co-expression of PDGFR-alpha was observed in three cases. Four cases showed expression of SCF, and c-Kit was observed only in one case that also expressed SCF. Generally, immunoreaction predominates in the glial component. The mutational analysis of PDGFR-alpha showed the presence of an IVS17-50insT intronic insertion in two cases, one of them also with a 2472C > T silent mutation; this silent mutation was also found in another case. Glioma cell line analysis of IVS17-50insT insertion showed no influence on PDGFR-alpha gene splicing. No mutations were detected in c-kit and B-RAF oncogenes. Our results indicate that activating mutations of PDGFR-alpha, c-kit and B-RAF are absent in gliosarcomas. Nevertheless, the presence of a PDGFR-a/PDGFA and c-Kit/SCF autocrine/paracrine stimulation loop in a proportion of cases, supports the potential role of specific tyrosine kinase inhibitors in the treatment of gliosarcomas.
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PMID:Molecular characterization of PDGFR-alpha/PDGF-A and c-KIT/SCF in gliosarcomas. 1637 64

Angiogenesis and signaling through the RAF/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK cascade have been reported to play important roles in the development of hepatocellular carcinomas (HCC). Sorafenib (BAY 43-9006, Nexavar) is a multikinase inhibitor with activity against Raf kinase and several receptor tyrosine kinases, including vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor receptor (PDGFR), FLT3, Ret, and c-Kit. In this study, we investigated the in vitro effects of sorafenib on PLC/PRF/5 and HepG2 HCC cells and the in vivo antitumor efficacy and mechanism of action on PLC/PRF/5 human tumor xenografts in severe combined immunodeficient mice. Sorafenib inhibited the phosphorylation of MEK and ERK and down-regulated cyclin D1 levels in these two cell lines. Sorafenib also reduced the phosphorylation level of eIF4E and down-regulated the antiapoptotic protein Mcl-1 in a MEK/ERK-independent manner. Consistent with the effects on both MEK/ERK-dependent and MEK/ERK-independent signaling pathways, sorafenib inhibited proliferation and induced apoptosis in both HCC cell lines. In the PLC/PRF/5 xenograft model, sorafenib tosylate dosed at 10 mg/kg inhibited tumor growth by 49%. At 30 mg/kg, sorafenib tosylate produced complete tumor growth inhibition. A dose of 100 mg/kg produced partial tumor regressions in 50% of the mice. In mechanism of action studies, sorafenib inhibited the phosphorylation of both ERK and eIF4E, reduced the microvessel area (assessed by CD34 immunohistochemistry), and induced tumor cell apoptosis (assessed by terminal deoxynucleotidyl transferase-mediated nick end labeling) in PLC/PRF/5 tumor xenografts. These results suggest that the antitumor activity of sorafenib in HCC models may be attributed to inhibition of tumor angiogenesis (VEGFR and PDGFR) and direct effects on tumor cell proliferation/survival (Raf kinase signaling-dependent and signaling-independent mechanisms).
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PMID:Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. 1717 82

The activation or the inhibition of melanocyte-specific receptors offers novel means of augmenting normal melanocyte function, skin color, and photoprotection, or treating melanocytic disorders, namely at this time, metastatic melanoma. Melanocyte-specific receptors include melanocortin-1 (MCR1) and melatonin receptors. Other receptors that play an important role in melanoma progression are G-protein couple receptors such as Frizzled 5 and receptor tyrosine kinases such as c-Kit and hepatocyte growth factor (HGF) receptor. These receptors activate two crucial cell-signaling pathways, RAS/RAF/MEK/ERK and PI3K/AKT, integral to melanoma cell survival, and can serve as targets for therapy of disseminated melanoma. Activation of death receptors is another pathway that can be exploited with targeted therapeutics to control advanced melanoma. This article reviews the current understanding of melanocyte receptors, their agonists and inhibitors, and their potential to treat the melanocytic pathology.
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PMID:Melanocyte receptors: clinical implications and therapeutic relevance. 1790 13

Chemotherapy, biological agents or combinations of both have had little impact on survival of patients with metastatic melanoma. Advances in understanding the genetic changes associated with the development of melanoma resulted in availability of promising new agents that inhibit specific proteins up-regulated in signal cell pathways or inhibit anti-apoptotic proteins. Sorafenib, a multikinase inhibitor of the RAF/RAS/MEK pathway, elesclomol (STA-4783) and oblimersen (G3139), an antisense oligonucleotide targeting anti-apoptotic BCl-2, are in phase III clinical studies in combination with chemotherapy. Agents targeting mutant B-Raf (RAF265 and PLX4032), MEK (PD0325901, AZD6244), heat-shock protein 90 (tanespimycin), mTOR (everolimus, deforolimus, temsirolimus) and VEGFR (axitinib) showed some promise in earlier stages of clinical development. Receptor tyrosine-kinase inhibitors (imatinib, dasatinib, sunitinib) may have a role in treatment of patients with melanoma harbouring c-Kit mutations. Although often studied as single agents with disappointing results, new targeted drugs should be more thoroughly evaluated in combination therapies. The future of rational use of new targeted agents also depends on successful application of analytical techniques enabling molecular profiling of patients and leading to selection of likely therapy responders.
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PMID:Small molecules and targeted therapies in distant metastatic disease. 1961 96

Carcinoma of the biliary tree are rare tumors of the gastrointestinal tract with worldwide rising incidence for intrahepatic cholangiocarcinoma during the last years. Although complete surgical resection is the only curative approach, this can be accomplished in a minority of patients, since most of them present with advanced disease. In addition, those patients who have undergone complete surgical resection experience a high tumor recurrence rate. Non-resectable biliary tract cancer is associated with a poor prognosis due to wide resistance to chemotherapeutic agents and radiotherapy. It is therefore essential to search for new therapeutical approaches. After several years of preclinical research, the first clinical study data are now available for this tumor entity. Inhibitors of the epidermal growth factor receptor (EGFR) family, such as erlotinib, cetuximab, and lapatinib were recently investigated. Furthermore, bortezomib, an inhibitor of the proteasome, imatinib mesylate, an inhibitor of c-kit-R, bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF), and sorafenib (BAY 43-9006), a multiple kinase inhibitor that blocks not only receptor tyrosine kinases but also serine/threonine kinases along the RAS/RAF/MEK/ERK pathway, were studied, as well. Although early evidence of antitumor activity was seen, the results are still preliminary and require further investigations.
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PMID:Molecular targeted therapy of biliary tract cancer--results of the first clinical studies. 2038 63

Sorafenib, a molecular-targeted agent that inhibits tumor cell proliferation and angiogenesis by inhibiting RAF serine-threonine kinase and VEGF, PDGF, Flt-3, c-Kit receptor tyrosine kinase, was approved in Europe and North America in 2007 and in Japan on May 20, 2009. In the 10 months since its approval, sorafenib has been prescribed for more than 3,700 patients with advanced hepatocellular carcinoma (HCC), and its efficacy has been confirmed in many cases. According to the consensus statements of the Japan Society of Hepatology in 2010, sorafenib is recommended for advanced HCC with extrahepatic spread or major vascular invasion such as invasion of the 1st branch of the portal vein or the main portal branch of the portal vein in patients with Child-Pugh A liver function. In addition to that, transcatheter arterial chemoembolization (TACE) or hepatic arterial infusion chemotherapy (HAIC) refractory HCC patients with Child-Pugh A liver function are also candidates of sorafenib monotherapy as a second-line treatment option. To date, 15 cases with complete remission (CR) to sorafenib in metastatic advanced HCC patients have been reported in Japan, an event that is rarely reported in other countries. Of the 90 cases treated by ourselves, 2 achieved CR. Factors indicating systemic cancer spread, including multiple liver lesions, lymph node metastases, adrenal metastases, lung metastases and vascular invasion, were completely absent in both cases of CR by 2 and 1 year, respectively. Similarly, three tumor markers (AFP, PIVKA-II, and AFP-L3) completely returned to normal values. Although cases of CR are rare, it seems that there might be racial differences in terms of gene mutations. Clinical trials for other molecular-targeted agents, including sunitinib, brivanib, or linifanib, are ongoing and their outcomes are eagerly awaited. According to a subanalysis of the SHARP study, it is expected that sorafenib in combination with resection, ablation, TACE or HAIC will markedly prolong the overall survival in early-, intermediate- and advanced- stage HCCs.
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PMID:Positioning of a molecular-targeted agent, sorafenib, in the treatment algorithm for hepatocellular carcinoma and implication of many complete remission cases in Japan. 2061 99

Immunotherapy and chemotherapy benefit few patients with metastatic melanoma, and even fewer experience durable survival benefit. These poor results may come from treating all melanomas as though they are biologically homogeneous. Recently, it has been shown that targeting specific activated tyrosine kinases (oncogenes) can have striking clinical benefits in patients with melanoma. In 2002, a V600E mutation of the BRAF serine/threonine kinase was described as present in more than 50% of all melanomas. The mutation appeared to confer a dependency by the melanoma cancer cell on activated signaling through mitogen-activated protein kinase pathway. The frequency and focality of this mutation (>95% of all BRAF mutations being at V600 position) suggested its importance in melanoma pathophysiology and potential as a target for therapy. The recent results of a phase 1 study with PLX4032/RG7204, a small molecule RAF inhibitor, confirm this hypothesis. Mucosal and acral-lentiginous melanomas, comprising 3% of all melanomas, frequently harbor activating mutations of c-kit and drugs targeting this mutation seem to confer similar benefits for these types of tumors. Here we provide an overview of the targeted therapy development in melanoma with emphasis on BRAF inhibition because of its prevalence and possibility of transforming the care of many melanoma patients.
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PMID:Targeted molecular therapy in melanoma. 2105 Oct 14

Oral mucosal melanoma (OMM) is a fatal sarcoma of unknown etiology. Histological morphology and genetic events are distinct from those of its cutaneous counterpart. Mutation and up-regulation of c-kit has been identified in OMM which may activate downstream molecules such as RAS and RAF. These molecules are involved in the mitogen-activated protein kinase (MAPK) pathway leading to tremendous cell proliferation and survival. NRAS and BRAF mutation and protein expression have been studied in other melanoma subtypes. The purpose of this study was to determine RAS protein expression and NRAS and BRAF mutation in 18 primary OMM cases using immunohistochemistry and mutation analysis. Results showed that RAS is intensely expressed in both in situ and invasive OMMs. However, NRAS mutation was only observed in 2/15 polymerase chain reaction (PCR) amplified cases both of which were silent mutations. On the other hand, BRAF missense mutations were observed only in 1/15 cases with PCR amplification. NRAS and BRAF mutations were independent from previously reported c-kit mutations. The classical V600E BRAF mutation was not found; instead a novel V600L was observed suggesting that the oncogenic event in OMM is different from that in skin melanoma. The low frequency of NRAS and BRAF mutations indicate that these genes are not common, but probable events in OMM pathogenesis, most likely independent of c-kit mutation.
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PMID:NRAS and BRAF mutation frequency in primary oral mucosal melanoma. 2175 Aug 66

Angiogenesis and signaling through the RAS/RAF/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK cascade have been reported to play important roles in the development of hepatocellular carcinoma (HCC). Sorafenib (Nexavar), a novel bi-aryl urea BAY 43-9006, is an orally administered multikinase inhibitor with activity against RAS/RAF kinases multikinase inhibitor with activity against RAF kinases and several receptor tyrosine kinases, including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), FLT3, Ret, and c-Kit. It is involved in angiogenic pathway and cell proliferation. Sorafenib has demonstrated potent anti-tumor activity in in vitro studies, preclinical xenograft models of different tumor types and human clinical trials. This review summarizes the history of sorafenib from its discovery by the medicinal chemistry approach through to clinical development and ongoing trials on the combination between sorafenib and trans-arterial chemoembolization (TACE) in HCC patients.
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PMID:Sorafenib (BAY 43-9006) in hepatocellular carcinoma patients: from discovery to clinical development. 2221 62


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