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)

Imatinib mesylate (IM), is a selective and competitive inhibitor of tyrosine kinases, including BCR-ABL, ABL, KIT, and the platelet-derived growth factor receptors (PDGF-R). It binds to the ATP-binding site of the target kinase and prevents the transfer of phosphate from ATP to the tyrosine residues of various substrates. At oral doses of 200-600 mg, the majority of patients with chronic myeloid leukaemia, Philadelphia chromosome-positive acute lymphoblastic leukemia expressing the BCR-ABL fusion protein and gastrointestinal stromal tumours (GIST) achieve a bio-molecular and clinical response, frequently complete, associated with limited toxicity. Several other human cancers, as small-cell lung carcinoma, melanoma, seminoma, some sarcomas, and adenoid cystic carcinomas may over-express KIT or PDGF-R, and clinical trials to evaluate the role of IM in the treatment of such cancers are currently ongoing. We determined c-KIT with Dako CD 117 antibody in 5 cases of advanced ocular melanoma (OM) and we found positive immuno-reactivity for CD 117 in three patients. We treated all patients with palliative-use IM at the oral dose of 400 mgr daily. We obtained in expressing positive immuno-reactivity for CD 117 patients: a reduction of malignant ascites in one, a partial remission in the neck nodes in another, and progression of liver metastases in the third. Evidences of progression has been reported in the other two patients expressing negative immuno-reactivity for CD 117. We conclude that the effect of IM should be assessed only in OM with positive immuno-histochemical c-kit (CD 117) expression. IM might be a potential therapeutic strategy for these patients.
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PMID:Tyrosine kinase inhibitor imatinib mesylate as anticancer agent for advanced ocular melanoma expressing immunoistochemical C-KIT (CD 117): preliminary results of a compassionate use clinical trial. 1676

We describe a case of coexisting BCR-ABL negative myeloproliferative disorder and precursor T-cell lymphoblastic lymphoma associated with t(8;13) involving FGFR1 at 8p11 in a 14-year-old boy who presented with generalized lymphadenopathy and an abdominal mass. JAK2 mutation and FIP1L1-PDGFRalpha were not detected. RT-PCR revealed the ZNF198-FGFR1 fusion transcript in both the bone marrow (BM) and lymph node (LN) of the patient at diagnosis. Of interest, reciprocal FGFR1-ZNF198 fusion transcript was demonstrated in the BM but not LN. Also differential clonal TcRgamma gene rearrangements in the BM and LN samples were observed. These findings provide novel insights into the genetic pathogenesis.
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PMID:Clonal evolution of 8p11 stem cell syndrome in a 14-year-old Chinese boy: a review of literature of t(8;13) associated myeloproliferative diseases. 1677 24

Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the gastrointestinal tract. Most of them have an activating mutation of KIT or PDGFRalpha tyrosine-kinase receptors. Imatinib is a selective tyrosine-kinase inhibitor of ABL, KIT and PDGFR, and provides a clinical benefit in about 85% of patients with advanced GIST. Unfortunately, secondary resistance following initial responses occurs in most of the cases, and molecular mechanisms are poorly understood. We sequenced KIT and PGDFRalpha exons from one patient with GIST before and after the development of imatinib resistance. We identified, in addition to a primary mutation in exon 9, a secondary mutation in KIT exon 13 (first kinase domain) in the resistant sample. We demonstrate for the first time the feasibility of sequencing such samples removed by non-surgical biopsies during imatinib therapy. Such a approach, far less invasive than surgery and combined with sequencing, will likely help in better tailoring the treatment of advanced GISTs and understanding the mechanisms of resistance and response to imatinib.
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PMID:Acquired resistance to imatinib and secondary KIT exon 13 mutation in gastrointestinal stromal tumour. 1678 29

The Ras/Raf/MEK/ERK and PI3K/PTEN/AKT signaling cascades play critical roles in the transmission of signals from growth factor receptors to regulate gene expression and prevent apoptosis. Components of these pathways are mutated or aberrantly expressed in human cancer (e.g., Ras, B-Raf, PI3K, PTEN, Akt). Also, mutations occur at genes encoding upstream receptors (e.g., EGFR and Flt-3) and chimeric chromosomal translocations (e.g., BCR-ABL) which transmit their signals through these cascades. These pathways interact with each other to regulate growth and in some cases tumorigenesis. For example, in some cells, PTEN mutation may contribute to suppression of the Raf/MEK/ERK cascade due to the ability of elevated activated Akt levels to phosphorylate and inactivate Raf-1. We have investigated the genetic structures and functional roles of these two signaling pathways in the malignant transformation and drug resistance of hematopoietic, breast and prostate cancer cells. Although both of these pathways are commonly thought to have anti-apoptotic and drug resistance effects on cells, they display different cell-lineage-specific effects. Induced Raf expression can abrogate the cytokine dependence of certain hematopoietic cell lines (FDC-P1 and TF-1), a trait associated with tumorigenesis. In contrast, expression of activated PI3K or Akt does not abrogate the cytokine dependence of these hematopoietic cell lines, but does have positive effects on cell survival. However, activated PI3K and Akt can synergize with activated Raf to abrogate the cytokine dependence of another hematopoietic cell line (FL5.12) which is not transformed by activated Raf expression by itself. Activated Raf and Akt also confer a drug-resistant phenotype to these cells. Raf is more associated with proliferation and the prevention of apoptosis while Akt is more associated with the long-term clonogenicity. In breast cancer cells, activated Raf conferred resistance to the chemotherapeutic drugs doxorubicin and paclitaxel. Raf induced the expression of the drug pump Mdr-1 (a.k.a., Pgp) and the Bcl-2 anti-apoptotic protein. Raf did not appear to induce drug resistance by altering p53/p21Cip-1 expression, whose expression is often linked to regulation of cell cycle progression and drug resistance. Deregulation of the PI3K/PTEN/Akt pathway was associated with resistance to doxorubicin and 4-hydroxyl tamoxifen, a chemotherapeutic drug and estrogen receptor antagonist used in breast cancer therapy. In contrast to the drug-resistant breast cancer cells obtained after overexpression of activated Raf, cells expressing activated Akt displayed altered (decreased) levels of p53/p21Cip-1. Deregulated expression of the central phosphatase in the PI3K/PTEN/Akt pathway led to breast cancer drug resistance. Introduction of mutated forms of PTEN, which lacked lipid phosphatase activity, increased the resistance of the MCF-7 cells to doxorubicin, suggesting that these lipid phosphatase deficient PTEN mutants acted as dominant negative mutants to suppress wild-type PTEN activity. Finally, the PI3K/PTEN/Akt pathway appears to be more prominently involved in prostate cancer drug resistance than the Raf/MEK/ERK pathway. Some advanced prostate cancer cells express elevated levels of activated Akt which may suppress Raf activation. Introduction of activated forms of Akt increased the drug resistance of advanced prostate cancer cells. In contrast, introduction of activated forms of Raf did not increase the drug resistance of the prostate cancer cells. In contrast to the results observed in hematopoietic cells, Raf may normally promote differentiation in prostate cells which is suppressed in advanced prostate cancer due to increased expression of activated Akt arising from PTEN mutation. Thus in advanced prostate cancer it may be advantageous to induce Raf expression to promote differentiation, while in hematopoietic cancers it may be beneficial to inhibit Raf/MEK/ERK-induced proliferation. These signaling and anti-apoptotic pathways can have different effects on growth, prevention of apoptosis and induction of drug resistance in cells of various lineages which may be due to the expression of lineage-specific factors.
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PMID:Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. 1685 53

A growing number of tumors are characterized by simple genetic changes that activate important biochemical pathways, which are involved in their pathogenesis. These findings have led to the concept of targeted small molecule inhibitor treatment. The prototype for this type of therapy has been treatment of chronic myelogenous leukemia with imatinib mesylate (Gleevec), which targets BCR-ABL kinase. More recently, imatinib has been used to inhibit KIT in gastrointestinal (GI) stromal tumor, a mesenchymal tumor that arises in the GI tract. Furthermore, it has been possible to target EGFR in non-small-cell lung cancer with gefitinib and erlotinib. While initial results have been encouraging, resistance to small molecule kinase inhibitors is a substantial drawback. This paper focuses on what is known about mechanisms of resistance in the treatment of solid tumors by small molecule kinase inhibitors.
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PMID:Mechanisms of resistance to small molecule kinase inhibition in the treatment of solid tumors. 1692 45

Molecular targeting of protein kinases is a new paradigm in the treatment of cancer. The clinical efficacy of low-molecular weight inhibitors of ABL, stem-cell growth-factor receptor, and the epidermal growth factor receptor in different tumor types is witness to the power of this approach. The presence of activating mutations of a kinase, or an increased gene copy number, might anticipate tumor responsiveness to its targeting. Thyroid cancer is the most prevalent endocrine malignancy and is frequently associated with the oncogenic conversion of two specific protein kinases, RET and BRAF. Small-molecule inhibitors of both kinases have already reached the clinical testing stage. Protein kinases other than RET and BRAF are also being evaluated for their potential in thyroid-cancer treatment.
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PMID:Drug insight: Small-molecule inhibitors of protein kinases in the treatment of thyroid cancer. 1693 52

Fusion genes derived from the platelet-derived growth factor receptor beta (PDGFRB) or alpha (PDGFRA) play an important role in the pathogenesis of BCR-ABL-negative chronic myeloproliferative disorders (CMPDs). These fusion genes encode constitutively activated receptor tyrosine kinases that can be inhibited by imatinib. Twelve patients with BCR-ABL-negative CMPDs and reciprocal translocations involving PDGFRB received imatinib for a median of 47 months (range, 0.1-60 months). Eleven had prompt responses with normalization of peripheral-blood cell counts and disappearance of eosinophilia; 10 had complete resolution of cytogenetic abnormalities and decrease or disappearance of fusion transcripts as measured by reverse transcriptase-polymerase chain reaction (RT-PCR). Updates were sought from 8 further patients previously described in the literature; prompt responses were described in 7 and persist in 6. Our data show that durable hematologic and cytogenetic responses are achieved with imatinib in patients with PDGFRB fusion-positive, BCR-ABL-negative CMPDs.
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PMID:Durable responses to imatinib in patients with PDGFRB fusion gene-positive and BCR-ABL-negative chronic myeloproliferative disorders. 1696 Jan 51

Recent studies have reported that imatinib mesylate, a kinase inhibitor that targets the intracellular tyrosine kinase BCR-ABL and the platelet derived growth factor (PDGF) receptor, is an effective inhibitor of the macrophage colony stimulating factor (M-CSF) receptor, c-FMS. Given that M-CSF signalling through c-FMS plays an important role in osteoclast biology, we speculated that blocking such a pathway with imatinib may modulate osteoclast activity. Using a cell model of mature rabbit osteoclasts, we thus investigated the effect of imatinib on in vitro osteoclast apoptosis and bone resorbing activity. Our findings demonstrate that imatinib dose-dependently stimulates osteoclast apoptosis, a phenomenon which is blocked by the caspase I inhibitor Z-VAD-fmk. The ability of imatinib to enhance osteoclast cell death was accompanied by a dose-dependent inhibition of osteoclast bone resorbing activity. Imatinib was also found to inhibit M-CSF-induced osteoclast survival as well as M-CSF-induced osteoclast bone resorbing activity, but was without effect on interleukin 1alpha (IL-1alpha) and receptor activator of nuclear factor kappa B ligand (RANKL)-induced inhibition of osteoclasts apoptosis, further supporting the hypothesis that imatinib may affect mature osteoclasts through the inhibition of c-FMS. Taken together, these results suggest that imatinib could be of clinical value in treating diseases where bone destruction can occur due to excessive M-CSF production such as osteoporosis, inflammatory-and tumor-induced osteolysis.
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PMID:Imatinib mesylate (Gleevec) enhances mature osteoclast apoptosis and suppresses osteoclast bone resorbing activity. 1704 13

Myeloid malignancies are frequently associated with translocations and mutations of tyrosine kinase genes. Fusion genes involving ABL, ARG, PDGFRs, JAK2, SYK, TRKC, and FGFRs, and gain-of-function mutations of FLT3, KIT and JAK2 have been detected at various rates in myeloproliferative disease and acute myeloid leukemia. Furthermore, abnormal overexpression of tyrosine kinases such as FLT3 has also been reported. These gene products are constitutively activated and potentially transform hematopoietic cells by augmentation of proliferation and enhanced viability. Since the fusion or mutation of tyrosine kinase is a primary and central event in chronic myeloproliferative diseases, targeting the kinase activity has been thought to be an ideal intervention to treat these diseases. The clinical success of imatinib for chronic myeloid leukemia has made this idea a reality, and has accelerated the development of new tyrosine kinase inhibitors (TKIs). Challenging studies with TKIs have also been reported for acute myeloid leukemia. This review will focus on recent trials of TKIs against oncogenic tyrosine kinases (ABL, PDGFRs, FLT3 and KIT) in myeloid malignancies.
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PMID:Developing target therapy against oncogenic tyrosine kinase in myeloid maliganacies. 1707 49

"Oncogene addiction" describes an unexplained dependency of cancer cells on a particular cellular pathway for survival or proliferation. We report that differential attenuation rates of prosurvival and proapoptotic signals in oncogene-dependent cells contribute to cell death following oncogene inactivation. Src-, BCR-ABL-, and EGF receptor-dependent cells exhibit a similar profile of signal attenuation following oncogene inactivation characterized by rapid diminution of phospho-ERK, -Akt, and -STAT3/5, and a delayed accumulation of the proapoptotic effector phospho-p38 MAPK. These findings implicate a transient imbalance in survival and apoptotic oncogenic outputs in the apoptotic response to oncogene inactivation. Moreover, these observations implicate a common profile of signal attenuation for multiple oncogenes and suggest that "addiction" associated with apoptosis reflects an active rather than a passive process.
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PMID:A common signaling cascade may underlie "addiction" to the Src, BCR-ABL, and EGF receptor oncogenes. 1709 54


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