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)

Imatinib mesilate, which efficiently inhibits BCR-ABL,and KIT as well as platelet-derived growth factor receptor (PDGF-R) kinases, is highly effective for clinical treatment of CML, Ph+ALL, and advanced GIST with good tolerability, respectively. Acquired resistance to the drug,however, becomes an clinically emerging problem with long-standing use. Meanwhile, sunitinib malate,which inhibits three VEGF-Rs and FLT 3 in addition to KIT as well as PDGF-R, was clinically evaluated in the phase II clinical trials for imatinib-resistant or intolerant GIST, and advanced renal cell carcinoma in Japan. Sunitinib is therapeutically effective for both on imatinib-resistant GIST and advanced renal cell carcinoma with modest tolerability, and is now under review for approval in Japan.
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PMID:[Imatinib . Sunitinib]. 1768 1

GIST are stromal tumors and the gastrointestinal tract (GIT) and some other organs of spindle-cell or epithelioid-cell structure expressing CD117 (C-kit, KIT), as well as those at different rates and in different combinations, CD34, smooth muscle and/or neurogenic differentiation antigens. It should be taken into account that CD117 are also expressed by melanomas, vascular, and some other tumors. The c-kit gene mutations leading to the expression and autoactivation of the tyrosine kinase receptor KIT underlie the oncogenesis of GIST, which results in enhanced proliferative activity and inhibited apoptosis. This is supported by successful chemotherapy for GIST with a KIT receptor inhibitor. The histogenesis of GIST is associated with GIT somatic stem, the Cajal cell precursors. Many GISTs behave like sarcomas and they are characterized by an infiltrating growth, hematogenic (mainly into the liver) and implantational (along the peritoneum) cancer spread. There are opinions that all such neoplasms are potentially malignany and small-sized GISTs are benign and have the minimum mitotic activity.
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PMID:[Clinical and morphological characteristics of gastrointestinal stromal tumors]. 1807 24

Constitutive activation of KIT receptor tyrosine kinase is a critical factor in the pathogenesis of gastrointestinal stromal tumors. Imatinib mesylate (IM, Glivec), a selective tyrosine kinase inhibitor, has been shown in clinical studies to work against such tumors. But there is little information on whether combination of IM and surgical treatment can prolong survival in cases with unresectable multiple liver metastases. We report a case of successful treatment of huge peritoneal metastasis from duodenal gastrointestinal stromal tumor resistant for IM. Therefore, we discuss some important implications. This 41-year-old Japanese man underwent a pancreaticoduodenectomy for GIST of the duodenum in January 2003. The postoperative course was good at first, but 3 months after the initial operation, MRI showed multiple liver metastases. The patient was treated with 400 mg of IM once daily with only weak liver dysfunction as a side effect. The initial response to treatment of CR continued for 20 months. Then huge mass of rt. abdomen appeared and gradually increased in size. Examination revealed that this mass is recurrent of peritoneal metastasis of the GIST. Extirpation was performed and this huge mass was recurrent GIST from omentum. Currently, IM is the first-line therapy for non-resectable GISTs, but a single agent therapy often leads to tumor resistance. IM-resistant GIST are treated with combination of novel molecular targeted-drug, RF, TAE, however, the effect is not enough. Surgical treatment is one of the successful treatments of huge peritoneal metastasis from duodenal gastrointestinal stromal tumor resistant for IM. Further examination in more cases of recurrent GIST is also necessary to estimate the effectiveness of treatment with IM.
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PMID:[Successful treatment of huge peritoneal metastasis from duodenal gastrointestinal stromal tumor resistant for imatinib mesylate]. 1821 26

Numerous options are currently available for tumour typing. This has raised intense interest in the elucidation of prognostic and predictive markers. A prognostic biomarker provides information about the patients overall cancer outcome, regardless of therapy, whilst a predictive biomarker gives information about the effect of a therapeutic intervention. A predictive biomarker can be a target for therapy. Amongst the genes that have proven to be of relevance are well-known markers such as ER, PR and HER2/neu in breast cancer, BCR-ABL fusion protein in chronic myeloid leukaemia, c-KIT mutations in GIST tumours and EGFR1 mutations in NSCLC. Several reasons for the difficult elucidation of new markers will be addressed including the involvement of cellular pathways in tumour biology instead of single genes and interference in disease outcome as a result of anticancer therapies. Future perspectives for the development of prognostic and predictive markers will be given.
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PMID:Prognostic versus predictive value of biomarkers in oncology. 1839 36

Imatinib is a tyrosine kinase inhibitor directed against the KIT and the PDGF-alpha receptors. Imatinib has proven efficacy in the treatment of metastatic GIST with a response rate achieving 70%, but treatment with imatinib alone is not curative. The median progression-free survival is about 2 years. In locally advanced GIST, primary treatment with imatinib proved to be safe and feasible in several cohort studies. The goal of any curatively intended surgical treatment for GIST is R0 resection. Therefore, neoadjuvant treatment with imatinib can be recommended if tumor-free margin resection is doubtful. After R0 resection of GISTs with intermediate or high risk of relapse, preliminary data indicate that imatinib administered for at least 1 year reduces the risk of relapse and may improve the prognosis. However, no mature survival data from randomized studies have been published thus far. Therefore adjuvant treatment with imatinib is not yet approved nor is it a standard of care at this stage. The inclusion of patients with intermediate- and high-risk resected GIST into clinical studies is strongly recommended.
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PMID:[Indications for pre- and postoperative treatment with imatinib for gastrointestinal stromal tumors]. 1854 19

Most GIST patients develop clinical resistance to KIT/PDGFRA tyrosine kinase inhibitors (TKI). However, it is unclear whether clinical resistance results from single or multiple molecular mechanisms in each patient. KIT and PDGFRA mutations were evaluated in 53 GIST metastases obtained from 14 patients who underwent surgical debulking after progression on imatinib or sunitinib. To interrogate possible resistance mechanisms across a broad biological spectrum of GISTs, inter- and intra-lesional heterogeneity of molecular drug-resistance mechanisms were evaluated in the following: conventional KIT (CD117)-positive GISTs with KIT mutations in exon 9, 11 or 13; KIT-negative GISTs; GISTs with unusual morphology; and KIT/PDGFRA wild-type GISTs. Genomic KIT and PDGFRA mutations were characterized systematically, using complementary techniques including D-HPLC for KIT exons 9, 11-18 and PDGFRA exons 12, 14, 18, and mutation-specific PCR (V654A, D820G, N822K, Y823D). Primary KIT oncogenic mutations were found in 11/14 patients (79%). Of these, 9/11 (83%), had secondary drug-resistant KIT mutations, including six (67%) with two to five different secondary mutations in separate metastases, and three (34%) with two secondary KIT mutations in the same metastasis. The secondary mutations clustered in the KIT ATP binding pocket and kinase catalytic regions. FISH analyses revealed KIT amplicons in 2/10 metastases lacking secondary KIT mutations. This study demonstrates extensive intra- and inter-lesional heterogeneity of resistance mutations and gene amplification in patients with clinically progressing GIST. KIT kinase resistance mutations were not found in KIT/PDGFRA wild-type GISTs or in KIT-mutant GISTs showing unusual morphology and/or loss of KIT expression by IHC, indicating that resistance mechanisms are fundamentally different in these tumours. Our observations underscore the heterogeneity of clinical TKI resistance, and highlight the therapeutic challenges involved in salvaging patients after clinical progression on TKI monotherapies.
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PMID:Heterogeneity of kinase inhibitor resistance mechanisms in GIST. 1862 23

GIST is the most common mesenchymal tumor of the gastrointestinal tract. The discovery of KIT proto-oncogene mutations in the pathogenesis of this tumor, and the development of imatinib mesylate, a specific inhibitor of KIT tyrosine kinase function have revolutionized the treatment of GIST. We present the clinical case of a patient with an upper digestive bleeding secondary to a jejunal GIST. Therapeutic options are highlighted.
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PMID:[Diagnosis and satisfactory surgical treatment of a jejunal stromal tumor]. 1879 72

As the range of receptor tyrosine kinase (RTK) inhibitors widens, a detailed understanding of the activating mechanisms of KIT/platelet-derived growth factor receptor (PDGFR)A and the related downstream pathways involved in the development and maintenance of GISTs is becoming increasingly important. We analysed areas with different histological response ratios in surgical specimens taken from imatinib-treated and untreated GIST patients in order to investigate KIT and PDGFRA expression/activation, the presence of their cognate ligands and the activation of downstream signalling, by means of biochemistry, immunohistochemistry and flow cytometry. All of the cases showed KIT and PDGFRA co-expression. In addition to the oncogenic activation of mutated receptors, activation of wild-type KIT and wild-type PDGFRA, sustained by heterodimerization and an autocrine-paracrine loop, was demonstrated by the presence of their specific ligands, stem cell factor (SCF) and PDGFA. To confirm RTK activation further, all of the samples (including those with the highest regression ratios) were investigated for downstream effectors, and all proved to have activated downstream signalling. The results show that after the mutated receptors are switched off, heterologous wild-type receptors become important in imatinib-treated GISTs as a means of maintaining signalling activation. Taken together, our findings suggest that drugs targeting wild-type receptors should be tested in imatinib-treated GIST patients.
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PMID:Oncogenic and ligand-dependent activation of KIT/PDGFRA in surgical samples of imatinib-treated gastrointestinal stromal tumours (GISTs). 1897 10

Neurofibromatosis type 1 or Recklinghausen disease is one of the most common hereditary autosomal dominant diseases. The disease-causing gene can be found on chromosome 17 as an NF1 tumor suppressor gene. The mutation of this gene leads to the loss of tumor suppressor function, which in turn causes the development of benign and malignant tumors. In 25% of the cases gastrointestinal manifestations are found, most often GIST. The close correlation of the two diseases are well known in the literature, there are more than 160 published cases. GIST develops in 7% of patients with neurofibromatosis, and among these patients the occurrence of NF1 is 150-180 times more frequent than in the general population. Neurofibromatosis associated with GIST is a different entity and, unlike sporadic GIST, it is usually multiplex and almost always develops in the small bowel. There is a slightly higher incidence among women than in men, and the disease develops at young age. Histological characteristics include spindle cell type, skeinoid fibers and frequent S100 positivity. Low mitotic activity usually suggests better prognosis. c-KIT and PDGFRA mutation is very rare, in agreement with the hypothesis that the pathogenesis of NF1-GIST is not c-KIT dependent. It is presumed that neurofibromatosis associated and sporadic GIST have different pathogenesis, and that the development of GIST tumor in neurofibromatosis is part of the hereditary disease. c-KIT and PDGFRA mutations--as shown in a few known cases--probably develop at a later step of tumor genesis. Imatinib, which has revolutionized the therapy of GIST, cannot be used in this patient group, however, as of today not enough information is available.
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PMID:[Gastrointestinal stromal tumors in neurofibromatosis type 1]. 1914 98

Advances in the field of GIST accumulate very rapidly. The objective of this short review is to underline their consequences for the diagnostic practice and for the understanding of their pathogenesis. The diagnosis of GIST still relies on histology and immunohistochemistry; this is only in the case of the very rare KIT-negative tumors that other markers (such as DOG-1 and PKCtheta) have to be considered and that the identification of mutations of KIT et PDGRA may have a diagnostic interest. A new prognostic classification of GIST has been proposed: it acknowledges the existence of truly benign GISTs and is adapted to the primary site of the lesion in order to underline the usually better prognosis of gastric GISTs. The search for mutations of KIT et PDGRA must be done in specialized laboratories. It is important for the evaluation of the sensivity to imatinib, and to the other targeted therapies which may find a role in the treatment of advanced tumors, especially of imatinib-resistent GISTs. Much remains to be done in order to decipher the molecular mechanisms responsible for tumor progression in GISTs: their knowledge will be important to validate new prognostic markers.
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PMID:[Gastrointestinal stroma tumors (GIST): what is new in 2009?]. 1923 89


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