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

Ewing sarcoma is a highly malignant tumor of bone preferentially arising in children and young adults. Its 5-year survival rate is only 50% despite the use of multimodal therapeutic approaches, requiring a search for new therapeutic targets and the development of novel therapeutic modalities. KIT and PDGFRs are type III receptor tyrosine kinases, and activating mutations in c-kit (which encodes KIT) and PDGFRs have been reported as oncogenic events in many malignancies. Imatinib is a selective inhibitor of KIT, PDGFR, and ABL tyrosine kinase activity and exerts different anti-tumor effects according to the regions of mutations in c-kit and PDGFR genes. Thus, we evaluated the immunohistochemical expression of KIT protein and the mutational status of exons 9, 11, 13, and 17 of the c-kit gene, exons 12 and 18 of the PDGFRA gene, and exon 12 of the PDGFRB gene in 71 formalin-fixed, paraffin-embedded Ewing sarcomas to increase our understanding of the potential, if any, of imatinib treatment for this malignancy. Of the 71 samples, 27 (38%) were immunohistochemically positive for KIT; however, activating mutations in c-kit were found in only 2 of 71 Ewing sarcomas (2.6%) within exon 9. No activating mutations in the PDGFRA and PDGFRB genes were found, but pleomorphism was identified in exon 18 of the PDGFRA gene. Our results for KIT protein expression agree with those of previous studies. This is the largest series of c-kit mutational analysis in Ewing sarcoma to date, and the results definitively show that c-kit activating mutations are not coincident with KIT protein expression in Ewing sarcoma in most samples. These findings imply other mechanisms for KIT activity and leave open the question of whether imatinib would be efficacious in the treatment of Ewing sarcoma.
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PMID:Protein expression of KIT and gene mutation of c-kit and PDGFRs in Ewing sarcomas. 1729 67

The incidence of gastrointestinal stromal tumors (GISTs) in children is exceptionally low. However, during the last decade these tumors attracted increasing attention, because they were found to express the cell surface transmembrane receptor kit (CD117) that has tyrosine kinase activity. This tyrosine kinase can be semi-selectively inhibited by signal transduction inhibitors such as imatinib mesylate (Glivec), which is a competitive inhibitor of c-kit, c-abl, platelet-derived growth factor receptor-alpha (PDGFR-alpha) and PDGFR-beta, and abl-related gene (arg). The authors present the clinical, radiographic, and pathological findings of 4 children who were diagnosed with gastric GIST. One of them had an incomplete Carney triad including GIST and mediastinal paraganglioma. All 4 patients presented with anemia and anemia-related symptoms and underwent total resection of the tumor. One patient received additional chemotherapy (in the pre-imatinib era) and 2 patients received a short course of imatinib mesylate. With a follow-up of 116, 55, 23, and 10 months all patients are alive in first complete continuous remission. In children and adolescents, particularly in female patients, GISTs should be included in the differential diagnosis of anemia secondary to gastrointestinal hemorrhage. Complete surgical resection is the mainstay of treatment for this tumor, with imatinib mesylate restricted to patients with advanced or metastatic tumors. Since late recurrences (up to 30 years following initial diagnosis) are reported, a life-long follow-up is mandatory in these patients.
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PMID:Clinical, radiological, and pathological findings in four children with gastrointestinal stromal tumors of the stomach. 1745 92

The aminopyrimidine inhibitor AMN107 (Nilotinib) was rationally designed to antagonize the aberrant tyrosine kinase activity of Bcr-Abl-positive cells. We here evaluated, whether AMN107 is also able to induce apoptosis in Bcr-Abl-negative cells of lymphatic origin. The B-cell lines DOHH-2 and WSU-NHL and the T-cell lines Jurkat and HUT78 were incubated with increasing amounts of AMN107 corresponding to clinically achievable dosages. Subsequently, induced molecular changes were assessed by FACS analysis, Western blot, and enzyme activity assays. Although AMN107 exhibited only a minor apoptosis-inducing effect in the T-cell lines, it exerted a considerable, dose-dependent cytotoxicity in the B-cell lines. Using selective caspase-inhibitors, we show that apoptosis in responder cell lines critically relies on activation of caspase-6 and caspase-9. Cell lines sensitive and resistant towards AMN107 can be discriminated by their differential expression of Src-kinases. Although the AMN107-sensitive cell lines DOHH-2 and WSU-NHL exhibited low or no expression of the Src-kinases Lck, phosphorylated Lck, and Yes with a concomitant high expression of Hck, Lyn, and phosphorylated Lyn, the expression pattern of these kinases was inverse in the AMN107-resistant T-cell lines. In conclusion, this is the first report providing evidence that activity of AMN107 is not restricted to Bcr-Abl, c-Kit, or PDGFR-positive cells, but also extends to lymphatic cell lines of B-cell origin.
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PMID:The tyrosine kinase inhibitor AMN107 (Nilotinib) exhibits off-target effects in lymphoblastic cell lines. 1761 67

The tyrosine kinase receptor c-kit and its interaction with the ligand, stem cell factor (SCF), play an essential role in the developing testis. C-kit is important for the development of the Leydig cells and for the migration, proliferation and survival of spermatogonia. Platelet-derived growth factor (PDGF) and its tyrosine kinase receptor (PDGFR) are important for the development of Leydig cells and myoid cells. The chemotherapeutic agent, imatinib mesylate (STI571, Glivec; Novartis) inhibits both of these tyrosine kinase receptors. Three-day treatment of immature male rats (SD) with imatinib (150 mg/kg) on postnatal days 5-7 delayed the formation of germ-line stem cell pool, reduced proliferation of type A spermatogonia and induced germ cell apoptosis. PDGFR-mediated proliferation of mesenchymal myoid precursors was also decreased and the length of the seminiferous cord was reduced. However, at the age of 11 weeks the exposed animals had normal epididymal sperm counts, whereas plasma levels of luteinizing hormone and follicle stimulating hormone were significantly increased. Imatinib serves as a good tool to study postnatal formation of the male germ-line stem cell pool and factors determining the final testicular size. As development of the human testis is controlled by the same mechanisms, further studies with primate and human models are needed to explore whether imatinib affects the testis in children as well.
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PMID:Inhibition of tyrosine kinases PDGFR and C-Kit by imatinib mesylate interferes with postnatal testicular development in the rat. 1770 9

Developments in the knowledge of molecular biology of renal cell carcinoma (RCC) over the past 20 years have been identified. Angiogenesis is playing a key role in the physiopathology of RCC. Von Hippel-Lindau (VHL) alterations, HIFalpha accumulation and vascular endothelial growth factor (VEGF) overexpression are important mediators of this process. Several stategies have been developped to target angiogenesis for the treatment of metastatic RCC. These include inhibition of VEGF receptors (inhibition of the tyrosine kinase activity) or binding to the VEGF protein. Several additional kinases inhibitions including PDGF receptors are also targeted. Sunitinib (SU11248) is an orally biovailable small molecule that has demonstrated superiority over interferon-alpha for the treatment of metastatic RCC. In a recent randomized phase III study conducted in 750 patients, the response rate to sunitinib was 31% and to interferon 6%. The median of progression free survival (PFS) was 11 months for sunitinib and 5 months for interferon (p < 0.001). Sorafenib (BAY43-9006) was found to inhibit Raf1, but also VEGFR2 and 3, Flt3, PDGFR-a and b and c-kit, has been tested in a phase III study against placebo after one prior systemic therapy. The median of the time to progression (TTP) for sorafenib was 24 weeks versus 12 weeks for patients in the placebo arm (p = 0,01). Other molecules tested in metastatic RCC will be presented including axitinib, pazopanib and bevacizumab.
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PMID:[Angiogenesis and renal cell carcinoma]. 1784 9

An improved understanding of acute myelogenous leukemia (AML) over the past two decades has led to a characterization of associated recurring cytogenetic abnormalities. AML is often driven by the overexpression or constitutive activation of receptor tyrosine kinases such as Fms-like tyrosine kinase 3 (FLT3), which serves as a good therapeutic target. Millennium Pharmaceuticals Inc's tandutinib (MLN-518) is an orally active inhibitor of FLT3 kinase and family members PDGFR beta and c-Kit. Tandutinib inhibited FLT3 phosphorylation, downstream signaling and malignant growth in vitro and in animal models. The drug exhibited limited activity as a single agent in phase I and II clinical trials in patients with AML and myelodysplastic syndrome, but displayed promising antileukemic activity (90% complete remissions) in a phase I/II trial in patients with newly diagnosed AML when administered in combination with cytarabine and daunorubicin. Phase II clinical trials for tandutinib are ongoing in patients with AML or renal cell carcinoma.
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PMID:Tandutinib, an oral, small-molecule inhibitor of FLT3 for the treatment of AML and other cancer indications. 1817 63

Targeted therapies by means of compounds that inhibit a specific target molecule represent a new perspective in the treatment of cancer. In contrast to conventional chemotherapy which acts on all dividing cells generating toxic effects and damage of normal tissues, targeted drugs allow to hit, in a more specific manner, subpopulations of cells directly involved in tumor progression. Molecules controlling cell proliferation and death, such as Tyrosine Kinase Receptors (RTKs) for growth factors, are among the best targets for this type of therapeutic approach. Two classes of compounds targeting RTKs are currently used in clinical practice: monoclonal antibodies and tyrosine kinase inhibitors. The era of targeted therapy began with the approval of Trastuzumab, a monoclonal antibody against HER2, for treatment of metastatic breast cancer, and Imatinib, a small tyrosine kinase inhibitor targeting BCR-Abl, in Chronic Myeloid Leukemia. Despite the initial enthusiasm for the efficacy of these treatments, clinicians had to face soon the problem of relapse, as almost invariably cancer patients developed drug resistance, often due to the activation of alternative RTKs pathways. In this view, the rationale at the basis of targeting drugs is radically shifting. In the past, the main effort was aimed at developing highly specific inhibitors acting on single RTKs. Now, there is a general agreement that molecules interfering simultaneously with multiple RTKs might be more effective than single target agents. With the recent approval by FDA of Sorafenib and Sunitinib--targeting VEGFR, PDGFR, FLT-3 and c-Kit--a different scenario has been emerging, where a new generation of anti-cancer drugs, able to inhibit more than one pathway, would probably play a major role.
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PMID:From single- to multi-target drugs in cancer therapy: when aspecificity becomes an advantage. 1828 97

FUS1 is a novel tumor suppressor gene identified in the human chromosome 3p21.3 region where allele losses and genetic alterations occur early and frequently for many human cancers. Expression of FUS1 protein is absent or reduced in the majority of lung cancers and premalignant lung lesions. Restoration of wt-FUS1 function in 3p21.3-deficient non-small cell lung carcinoma cells significantly inhibits tumor cell growth by induction of apoptosis and alteration of cell cycle kinetics. Here we present recent findings indicating that FUS1 induces apoptosis through the activation of the intrinsic mitochondrial-dependent and Apaf-1-associated pathways and inhibits the function of protein tyrosine kinases including EGFR, PDGFR, AKT, c-Abl, and c-Kit. Intravenous administration of a nanoparticle encapsulated FUS1 expression plasmid effectively delivers FUS1 to distant tumor sites and mediates an antitumor effect in orthotopic human lung cancer xenograft models. This approach is the rationale for an ongoing FUS1-nanoparticle-mediated gene delivery clinical trial for the treatment of lung cancer.
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PMID:Tumor suppressor FUS1 signaling pathway. 1837 48

Imatinib mesylate (Glivec, STI 571; Novartis), a small-molecular analog of ATP that potently inhibits the tyrosine kinase activities of Bcr-Abl, PDGFR-alpha, PDGFR-beta, c-Fms, Arg and c-kit, is one of the novel molecularly targeted agents being introduced into cancer therapy. Stem cell factor (SCF)/c-kit and platelet-derived growth factor (PDGF) signaling pathways regulate postnatal formation of the pools of spermatogonial stem cells and Leydig cells in the rat testis. The effect of short postnatal imatinib exposure on fertility of the male rats and offspring of these animals were investigated. Imatinib significantly reduced the litter size sired by the treated animals and led to permanently slightly elevated serum levels of the gonadotropins. Testicular morphology and mRNA levels of ligands and receptors involved in stem cell factor/c-kit and PDGF signaling returned to control levels, and the offsprings were born healthy. Our findings indicate that treatment of cancer with certain molecularly targeted drugs may have latent effects on testicular development by inhibiting specific physiological signaling pathways.
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PMID:Adult reproductive functions after early postnatal inhibition by imatinib of the two receptor tyrosine kinases, c-kit and PDGFR, in the rat testis. 1847 95

The expression of c-kit, a protooncogene tyrosine kinase receptor (CD117), in phyllodes tumors of the breast has been the subject of recent investigations. We examined stromal c-kit expression by immunohistochemistry in 68 cases comprising fibroadenomas, fibroadenomas with cellular stroma, and benign, borderline, and malignant phyllodes tumors. Membrane staining was identified in the epithelium of 82% of cases, representing all diagnostic categories in the study. Membrane and cytoplasmic staining was detected in scant cells in the stroma in 74% of the cases in the study, again, across all diagnostic entities. However, when toluidine blue and tryptase staining was performed, the staining pattern matched that of c-kit in the number of cells and their distribution, thereby confirming the presence of mast cells and excluding any appreciable level of true stromal c-kit staining. One borderline and one malignant phyllodes tumor showed a diffuse weak stromal signal, which could not be accounted for by toluidine blue and tryptase. These cases were further tested for the presence of known activating mutations of c-kit and PDGFR-alpha, and yielded negative results. Our findings indicate that c-kit is an unlikely player in the pathogenesis of fibroepithelial lesions of the breast. The positive stromal staining suggested previously by other authors may be attributed to mast cells. C-kit, therefore, has neither a diagnostic nor a prognostic role in phyllodes tumors, and there is no rationale for the treatment of recurrent of malignant phyllodes tumor patients with tyrosine kinase inhibitors.
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PMID:Expression of c-kit in fibroepithelial lesions of the breast is a mast cell phenomenon. 1850 Feb 66


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