Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We performed immunohistochemical analysis for KIT in 365 soft tissue sarcomas. Most tumors evaluated were completely negative for KIT, including all cases of leiomyosarcoma, rhabdomyosarcoma, myxofibrosarcoma, liposarcoma, solitary fibrous tumor, synovial sarcoma, dermatofibrosarcoma protuberans, schwannoma, malignant peripheral nerve sheath tumor, clear cell sarcoma, low-grade endometrial stromal sarcoma, and follicular dendritic cell sarcoma. Tumors showing occasional immunoreactivity for KIT included extraskeletal myxoid chondrosarcoma (2/20), Ewing sarcoma/malignant primitive peripheral neuroectodermal tumor (4/20), melanotic schwannoma (3/5), metastatic melanoma (4/20), and angiosarcoma (5/20). In most cases, staining for KIT was focal. Rare tumor cells showing KIT positivity were identified in a small number of other tumors. This study demonstrates very limited expression of KIT in soft tissue tumors other than gastrointestinal stromal tumors and underscores the discriminatory value of KIT immunohistochemical analysis for differential diagnosis. As some of these findings differ markedly from previous reports, it is evident again that variations in immunohistochemical technique can lead to major discrepancies in positive staining. Since treatment eligibility for selective tyrosine kinase inhibitors such as STI571 hinges on positive immunostaining, standardization and reproducibility of meaningful results are critically important.
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PMID:Immunohistochemical staining for KIT (CD117) in soft tissue sarcomas is very limited in distribution. 1221 91

Imatinib (STI571 or CGP57148B) is an innovative treatment for tumours with a constitutively activated form of c-ABL, c-KIT, or PDGFR. Such tumours include Philadelphia-chromosome-positive (Ph-positive) leukaemias, gastrointestinal stromal tumours, and PDGFR-positive leukaemias. Diseases such as primary hypereosinophilia and dermatofibrosarcoma protuberans also seem to respond to imatinib. Clinical trials assessing the therapeutic effects of imatinib have shown that the drug is highly effective with few associated side-effects, achieving durable cytogenetic responses in many patients with chronic-phase BCR-ABL-positive leukaemias. However, the emergence of resistance, particularly in patients with acute leukaemias, has prompted intense research, and many are concerned about the future prospects for imatinib. The resistance has been found in patients with acute-phase disease, but may also occur in patients with chronic-phase disease. Two cellular mechanisms for resistance to imatinib have been identified: amplification of BCR-ABL gene and mutations in the catalytic domain of the protein. In addition, suboptimum inhibition of BCR-ABL in vivo could contribute to the selection of resistant cells. We have summarised all currently available data on resistance to imatinib, both published and unpublished, including the mechanisms of resistance identified so far, and their clinical relevance to the different forms of Ph-positive leukaemias is discussed. Furthermore, we discuss strategies to overcome or prevent the development of resistance.
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PMID:Molecular mechanisms of resistance to imatinib in Philadelphia-chromosome-positive leukaemias. 1257 49

Dermatofibrosarcoma protuberans (DFSP) is an aggressive spindle cell neoplasm. It is associated with the chromosomal translocation, t(17:22), which fuses the COL1A1 and PDGFbeta genes. We determined the characteristic gene expression profile of DFSP and characterized DNA copy number changes in DFSP by array-based comparative genomic hybridization (array CGH). Fresh frozen and formalin-fixed, paraffin-embedded samples of DFSP were analyzed by array CGH (four cases) and DNA microarray analysis of global gene expression (nine cases). The nine DFSPs were readily distinguished from 27 other diverse soft tissue tumors based on their gene expression patterns. Genes characteristically expressed in the DFSPs included PDGF beta and its receptor, PDGFRB, APOD, MEOX1, PLA2R, and PRKCA. Array CGH of DNA extracted either from frozen tumor samples or from paraffin blocks yielded equivalent results. Large areas of chromosomes 17q and 22q, bounded by COL1A1 and PDGF beta, respectively, were amplified in DFSP. Expression of genes in the amplified regions was significantly elevated. Our data shows that: 1) DFSP has a distinctive gene expression profile; 2) array CGH can be applied successfully to frozen or formalin-fixed, paraffin-embedded tumor samples; 3) a characteristic amplification of sequences from chromosomes 17q and 22q, demarcated by the COL1A1 and PDGF beta genes, respectively, was associated with elevated expression of the amplified genes.
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PMID:Gene expression patterns and gene copy number changes in dermatofibrosarcoma protuberans. 1463 10

Among novel promising approaches to anticancer therapy belongs the targeting inhibition of signal transduction. This review outlines present-day experiences with imatinib (Glivec), a potent inhibitor of the tyrosine kinases bcr-abl, c-kit and platelet-derived growth factor receptor kinase. Due to inhibition of bcr-abl tyroxine kinase, imatinib has rapidly become the standard therapy for chronic myelocytic leukemia; inhibition of c-kit receptor explains its effectivity in the treatment of patients with gastrointestinal stromal tumors. Another known target of imatinib is tyrosine kinase of PDGFR, which is activated in numerous malignancies, particularly in dermatofibrosarcoma protuberans. Discovery of the novel fusion gene in hypereosinophilic syndrome (FIPILI-PFGFRA, whose product is an imatinib sensitive protein kinase) permitted to treat successfully this event. Possible combination of imatinib with conventional chemotherapeutic drugs and other key signal transduction inhibitors are mentioned.
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PMID:[Imatinib--a new perspective in the treatment of tumors]. 1553 94

A subset of low-grade fibrosarcomas is composed of CD34-positive spindle cells. These include dermatofibrosarcoma, its morphologic variants, and its associated fibrosarcoma, solitary fibrous tumor, hemangiopericytoma and their malignant counterparts, and some cases of myxoinflammatory fibroblastic sarcoma. Dermatofibrosarcoma and related lesions are characterized by a t(17;22)(q22;q13) rearrangement resulting in fusion of the genes COL1A (17q21-22) and PDGFB1 (22q13). Solitary fibrous tumor displays varying cellularity and fibrosis and a peripheral hemangiopericytomatous pattern; most tumors formerly called hemangiopericytoma are now subsumed into the category of solitary fibrous tumor, although a few strictly defined examples are recognized; however, these are probably not composed of pericytes. Myofibroblastic malignancies are best identified by electron microscopy, with which varying degrees of differentiation, including the presence of fibronexus junctions, can be identified. Low-grade sarcomas showing myofibroblastic differentiation include myofibrosarcomas and inflammatory myofibroblastic tumors. Myofibrosarcomas are spindle cell neoplasms that occur in children or adults in the head and neck, trunk, and extremities as infiltrative neoplasms and that display a fascicular or fasciitis-like pattern with focal nuclear atypia and variable expression of myoid antigens. These sarcomas are prone to recurrence and a small number metastasize. Inflammatory myofibroblastic tumor (synonymous with inflammatory fibrosarcoma) is a neoplasm arising predominantly in childhood, and frequently in intraabdominal locations. It has spindle cells in fascicular, fasciitis-like and sclerosing patterns, with heavy chronic inflammation including abundant plasma cells. Many IMT have clonal chromosomal abnormalities involving 2p22-24, and fusion of the ALK gene with tropomyosin 3 (TPM3-ALK) or tropomyosin 4 (TPM4-ALK) is found in a subset.
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PMID:Low-grade sarcomas with CD34-positive fibroblasts and low-grade myofibroblastic sarcomas. 1576 78

The hallmark characteristics of cancer include an unrestrained proliferation involving activation of growth signals, loss of negative regulation and dysfunctional apoptotic pathways. Targeting abnormal cell signalling pathways should provide a more selective approach to cancer treatment than conventional cytotoxic chemotherapy. Tyrosine kinases play an essential role in the signalling pathways involved in the control of cellular proliferation and growth. Imatinib is a small-molecule tyrosine kinase inhibitor of the ABL fusion gene, platelet derived growth factor receptors (PDGFR) and KIT. This agent has demonstrated considerable activity in chronic myeloid leukaemia (CML) by inhibiting the BCR-ABL fusion protein and gastrointestinal stromal tumours (GISTs), which are predominantly driven by activating mutations in KIT. A number of other rare conditions are also responsive, for example, dermatofibrosarcoma protuberans, which is driven by a chromosomal translocation involving PDGF-B and Col1A1, resulting in overexpression of PDGF-B, and hypereosinophillic syndrome, which can be caused by activating PDGFR mutations. The pivotal registration study for newly diagnosed CML was a large randomised trial comparing 400 mg/day of imatinib to a combination of IFN-alpha and cytarabine, which demonstrated a significantly higher complete haematological and cytogenetic response rate in the imatinib arm. In the case of GIST a randomised study in patients with inoperable or metastatic disease explored doses of 400 - 600mg and reported a response rate of > 50% in each arm plus disease stabilisation and an improvement in performance status. Large randomised trials have subsequently been performed, comparing 400 with 800mg/day. The first to report indicates that the larger dose is associated with improved progression-free survival, although it is not yet known whether or not this will translate into a difference in overall survival. The most common KIT mutation involves exon 11 and is associated with a statistically significant better response and prognosis compared with other mutations or no detectable mutations. Mutational analysis is likely to become increasingly important in the selection of patients for neoadjuvant and adjuvant treatment and in helping to understand the nature of acquired resistance.
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PMID:The development and application of imatinib. 1579 12

The overexpression of phosphorylated signal transducer and activator of transcription-3 (p-STAT3) and phosphorylated extracellular signal-regulated kinase (p-ERK) have recently been shown to play an important role in the pathogenesis of various human tumors. However, the role of these two major signal transduction pathways in dermatofibrosarcoma protuberans (DFSP) remains unknown. This study was designed to investigate the significance of p-STAT3 and p-ERK expression in DFSP. The expressions of p-STAT3 and p-ERK were analyzed by immunohistochemical staining in formalin-fixed, paraffin-embedded tissue sections of human DFSP and dermatofibroma. Ten cases were positive for p-STAT3 expression in 14 cases of DFSP, however, only 5 cases were positive in 20 cases of dermatofibroma. Eleven out of 14 cases of DFSP expressed p-ERK, but only four cases were positive in 20 cases of dermatofibroma. The expressions of p-STAT3 and p-ERK were significantly higher than those in dermatofibroma (both p < 0.01). This study suggests that the overexpression of p-STAT3 and p-ERK may play a pivotal role in the oncogenesis of DFSP.
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PMID:Overexpression of phosphorylated-STAT3 and phosphorylated-ERK protein in dermatofibrosarcoma protuberans. 1670 90

Fusion of the collagen type I alpha 1 (COL1A1) gene with the platelet-derived growth factor beta chain (PDGFB) gene has been described in dermatofibrosarcoma protuberans. The abnormal fusion transcripts probably cause PDGFB and its receptor (platelet-derived growth factor receptor beta, PDGFRB) autocrine stimulation and cell proliferation, which are responsible for the development of dermatofibrosarcoma protuberans. A reverse transcription-polymerase chain reaction assay was performed to detect the COL1A1-PDGFB fusion transcripts in 57 samples. In addition, the PDGFB gene amplification and PDGFB/PDGFRB mRNA levels were quantified by a real-time PCR system for the samples in which the fusion transcripts had been successfully detected. The fusion transcripts were detected in 42 of 57 samples. Various exons of the COL1A1 gene were fused in frame with the PDGFB gene; exons 7 and 25 were found to be slightly more frequently involved than the other exons. The PDGFB gene amplification levels varied from 0.6 to 8.3 (mean 2.4) in 42 tumor samples and from 0.4 to 3.0 (mean 1.2) in 20 adjacent normal tissue samples. In the 20 paired samples, the PDGFB gene amplification in the tumor was significantly higher than that in the normal tissue. The presence of PDGFB and PDGFRB mRNAs was demonstrated in 26 and 21 of 26 cases, respectively. The PDGFB and PDGFRB mRNA expression levels showed a good correlation (r=0.76, P<0.0001). These results indicate that the fusion protein, which is processed by the COL1A1-PDGFB transcripts, can serve as a functional ligand for PDGFRB.
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PMID:Detection of COL1A1-PDGFB fusion transcripts and PDGFB/PDGFRB mRNA expression in dermatofibrosarcoma protuberans. 1743 12

Once a poorly understood pathologic entity, gastrointestinal stromal tumor (GIST) has emerged in recent years as a distinct oncologic-molecular paradigm that is now a leading model for kinase-targeted therapies in oncology. Most GISTs are KIT-expressing and KIT signaling-driven mesenchymal tumors, many of which have KIT-activating mutations. A small subset of GIST show activating mutations in PDGFRA, encoding a related member of the type III receptor tyrosine kinase family. The revelation of KIT expression as a diagnostic signature of GIST has not only revolutionized the pathologic criteria in classifying GIST, but also shed light on the histogenesis of these tumors. The similarities in KIT immunoreactivity and ultrastructural appearance between GISTs and the intestinal pacemaker, the interstitial cells of Cajal (ICC), suggested that GISTs derive from or differentiate toward the ICC lineage. KIT plays a significant role in proliferation, survival, and differentiation of hematopoietic stem cells, mast cells, melanocytes, and interstitial cells of Cajal; activating KIT mutations have been identified in tumors affecting most of these cell lineages. This review will include a summary of the biology behind the specific targeted therapies, emphasizing the central role of KIT and PDGFRA oncogenic mutations in GISTs and their clinical and pathologic correlates. The role of KIT immunohistochemistry vs mutation testing will be discussed, with an insight into the indications for KIT/PDGFRA genotyping in GIST. The morphologic and molecular changes that appear with imatinib treatment, such as response and acquired imatinib resistance, are being discussed. The success GIST story based on targeted molecular paradigm may be applied in other imatinib-responsive sarcoma, such as dermatofibrosarcoma protuberans.
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PMID:Targeted therapy of cancer: new roles for pathologists in identifying GISTs and other sarcomas. 1843 71

(1) Imatinib, a tyrosine kinase inhibitor, was first marketed for the treatment of chronic myeloid leukaemia and some gastrointestinal stromal tumours. Its indications have gradually expanded over the years. (2) There is no consensus treatment for adults with Philadelphia chromosome-positive acute lymphoblastic leukaemia. In a trial comparing imatinib versus chemotherapy as initial treatment for 55 patients, the haematological response rate was higher with imatinib. Non-comparative trials provided haematological response rates of about 90%, but it is not known whether or not this translates into a survival advantage. In three non-comparative trials including patients with relapsed or refractory disease after chemotherapy, 50% of patients showed a survival time of at least 7 months. In the absence of any direct comparisons, we do not know if this represents an improvement over the results obtained with the best palliative care. (3) The only potential cure for myelodysplastic syndromes is allogeneic haematopoietic stem cell transplantation but this is not always feasible. Some myelodysplastic syndromes are associated with myeloproliferation and PDGFR gene rearrangements; imatinib is the first drug available for these patients. The manufacturer has compiled data on 55 patients treated with imatinib. Most patients had a favourable haematological response, but no survival data were published. (4) The severity of the hypereosinophilic syndrome is highly variable. Forms associated with FIP1L1-PDGFRalpha gene rearrangements have a poor prognosis. Clinical evaluation of imatinib in this setting is based on a compilation of data concerning 176 treated patients. The haematological response rate was high in patients with the mutant gene, but it is not known whether this translated into increased survival. (5) Dermatofibrosarcoma protuberans is a rare form of mainly localised skin cancer. Treatment is based on surgical excision but relapses are frequent. In one series, 9 out of 12 patients treated with imatinib had at least a partial tumour response, making surgical excision possible in 3 cases. (6) Imatinib has diverse and frequent adverse effects; nausea and vomiting, oedema, fluid retention, cutaneous disorders and heart failure. There is some evidence pointing to a risk of urologic cancers and altered bone metabolism.
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PMID:Imatinib: new indication. New indications, but not robust evidence. 1862 99


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