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)

Angiogenesis is a strongly regulated process, which is dependent upon a complex interplay between inhibitory and stimulatory angiogenic factors. It is essential for tumor growth and metastasis: increased angiogenesis is correlated with poor prognosis in cancer patients. Many novel compounds that potently inhibit formation of neoplastic blood vessels have been recently developed. Major categories of angiogenesis antagonists include protease inhibitors, direct inhibitors of endothelial cell proliferation and migration, angiogenic growth factor suppressors, inhibitors of endothelial-specific integrin/survival signalling, copper chelators, and inhibitors with other specific mechanisms. There is increasing interest in developing angio-suppressive agents for colorectal cancer treatment. Some 20 direct and indirect antiangiogenesis drugs are currently being evaluated in clinical trials in colorectal cancer (CRC). Promising results have been reported. These include an increase in overall survival and reduction in the risk of death (Bevacizumab), reversal of cellular resistance (Cetuximab) and activity as second-line therapy in patients who have exhausted other available treatment options (Cetuximab, ABX-EGF, PTK-787, Gefitinib, Erlotinib). This review will outline the mechanisms of action of the principal antiangiogenic drugs, summarize the available data on the use of these new drugs in colorectal cancer, discuss their impact in clinical practice and offer a glimpse into how antiangiogenetic therapy will be integrated into the future care of patients with gastrointestinal cancers.
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PMID:Colorectal cancer and antiangiogenic therapy: what can be expected in clinical practice? 1589 May 25

Receptor and non-receptor tyrosine kinases (TKs) have emerged as clinically useful drug target molecules for treating gastrointestinal cancer. Imatinib mesilate (STI-571, Gleevec(TM)), an inhibitior of bcr-abl TK, which was primarily designed to treat chronic myeloid leukemia is also an inhibitor of c-kit receptor TK, and is currently the drug of choice for the therapy of metastatic gastrointestinal stromal tumors (GISTs), which frequently express constitutively activated forms of the c-kit-receptor. The epidermal growth factor receptor (EGFR), which is involved in cell proliferation, metastasis and angiogenesis, is another important target. The two main classes of EGFR inhibitors are the TK inhibitors and monoclonal antibodies. Gefitinib (ZD1839, Iressa(TM)) has been on trial for esophageal and colorectal cancer (CRC) and erlotinib (OSI-774, Tarceva(TM)) on trial for esophageal, colorectal, hepatocellular, and biliary carcinoma. In addition, erlotinib has been evaluated in a Phase III study for the treatment of pancreatic cancer. Cetuximab (IMC-C225, Erbitux(TM)), a monoclonal EGFR antibody, has been FDA approved for the therapy of irinotecan resistant colorectal cancer and has been tested for pancreatic cancer. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are critical regulators of tumor angiogenesis. Bevacizumab (Avastin(TM)), a monoclonal antibody against VEGF, was efficient in two randomized clinical trials investigating the treatment of metastatic colorectal cancer. It is also currently investigated for the therapy of pancreatic cancer in combination with gemcitabine. Other promising new drugs currently under preclinical and clinical evaluation, are VEGFR2 inhibitor PTK787/ZK 222584, thalidomide, farnesyl transferase inhibitor R115777 (tipifarnib, Zarnestra(TM)), matrix metalloproteinase inhibitors, proteasome inhibitor bortezomib (Velcade(TM)), mammalian target of rapamycin (mTOR) inhibitors, cyclooxygenase-2 (COX-2) inhibitors, platelet derived growth factor receptor (PDGF-R) inhibitors, protein kinase C (PKC) inhibitors, mitogen-activated protein kinase kinase (MEK) 1/2 inhibitors, Rous sarcoma virus transforming oncogene (SRC) kinase inhibitors, histondeacetylase (HDAC) inhibitors, small hypoxia-inducible factor (HIF) inhibitors, aurora kinase inhibitors, hedgehog inhibitors, and TGF-beta signalling inhibitors.
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PMID:Molecularly targeted therapy for gastrointestinal cancer. 1589 18

Non-small cell lung cancers (NSCLCs) with activating mutations in the kinase domain of the epidermal growth factor receptor (EGFR) demonstrate dramatic, but transient, responses to the reversible tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva). Some recurrent tumors have a common secondary mutation in the EGFR kinase domain, T790M, conferring drug resistance, but in other cases the mechanism underlying acquired resistance is unknown. In studying multiple sites of recurrent NSCLCs, we detected T790M in only a small percentage of tumor cells. To identify additional mechanisms of acquired resistance to gefitinib, we used NSCLC cells harboring an activating EGFR mutation to generate multiple resistant clones in vitro. These drug-resistant cells demonstrate continued dependence on EGFR and ERBB2 signaling for their viability and have not acquired secondary EGFR mutations. However, they display increased internalization of ligand-activated EGFR, consistent with altered receptor trafficking. Although gefitinib-resistant clones are cross-resistant to related anilinoquinazolines, they demonstrate sensitivity to a class of irreversible inhibitors of EGFR. These inhibitors also show effective inhibition of signaling by T790M-mutant EGFR and killing of NSCLC cells with the T790M mutation. Both mechanisms of gefitinib resistance are therefore circumvented by irreversible tyrosine kinase inhibitors. Our findings suggest that one of these, HKI-272, may prove highly effective in the treatment of EGFR-mutant NSCLCs, including tumors that have become resistant to gefitinib or erlotinib.
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PMID:Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. 1589 64

Gefitinib (Iressa), an epidermal growth factor receptor targeting drug, has been clinically useful for the treatment of patients with non-small cell lung cancer (NSCLC). Gefitinib is currently being applied in clinical studies as either a monotherapy, or as part of a combination therapy against prostate, head and neck, gastric, breast, and colorectal tumors. However, success rates vary between different tumor types, and thus it is important to understand which molecular target(s) are responsible for limiting the therapeutic efficacy of the drug. In this study, we ask whether expression of HER2 affects sensitivity to gefitinib in human lung cancer cells. We established two clones, LK2/HER2-32 and LK2/HER2-57, by transfecting HER2 cDNA into LK2, a NSCLC line with a low expression level of HER2. We observed no mutations in exons 18, 19, and 21 of EGFR gene in LK2, LK2/mock- and two HER2-trasfectants when we observed in-frame deletion mutations (E746-A750) adjacent to K745 in a gefitinib-sensitive NSCLC cell line, PC9. These LK2/HER2-32 and LK2/HER2-57 were much more sensitive to the cytotoxic effects of gefitinib than the parental LK2 lines. Treatment with 0.5 to 1 micromol/L gefitinib specifically blocked Akt activation in both HER2-transfectant lines, but not in the parental LK2 cells. Extracellular signal-regulated kinase-1/2 activation, however, was not blocked by gefitinib up to 10 micromol/L in either the parent or transfectant lines. Gefitinib was also shown to induce cell cycle arrest in the G1-S phase, and an accompanying increase of p27Kip1 was observed. LK2/HER2 transfectants showed constitutive formation of HER2/HER3 heterodimer, which were seen to associate with a regulatory subunit of phosphoinositide-3-kinase, p85alpha, when active. Treatment of LK2/HER2 cells with gefitinib markedly decreased the formation of HER2/HER3 heterodimers, HER3 basal phosphorylation, and the association of p85alpha with HER3. This study is the first to show that under basal growth conditions, HER2 sensitizes low-EGFR NSCLC cell lines to growth inhibition by gefitinib.
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PMID:HER2 overexpression increases sensitivity to gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, through inhibition of HER2/HER3 heterodimer formation in lung cancer cells. 1589 17

The EGFR-inhibition via tyrosine-kinase-inhibitor gefitinib (Iressa) constitutes a new way to treat non-small-cell lung cancer. Recent research results enable us to better understand the basics of molecular targeted therapy (MTT). These results are helpful to re-interpret the clinical results obtained so far for gefitinib and to consider for the first time in a predictive manner factors for the selection of patients suitable for therapy. Three case reports are presented in this paper which illustrate that -- with view to the results from translational research -- the use of gefitinib offers an efficient new therapeutic modality for the treatment of chemotherapy-resistant non-small-cell lung cancer.
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PMID:[Non-small-cell lung cancer third-line therapy with gefitinib]. 1590 97

In this study, we have characterized a panel of NSCLC cell lines with differential sensitivity to gefitinib for activating mutations in egfr, pik3ca, and k-ras, and basal protein expression levels of PTEN. The egfr mutant NSCLC cell line H1650 as well as the egfr wild type cell lines H292 and A431 were highly sensitive to gefitinib treatment, indicating that other factors determine gefitinib-sensitivity in egfr wild type cells. Activating k-ras mutations were specifically detected in gefitinib-resistant cells, suggesting that the occurrence of k-ras mutations is correlated with resistance to EGFR antagonists. No pik3ca mutations were detected within the panel of cell lines, and PTEN protein expression levels did not correlate with gefitinib sensitivity. Gefitinib effectively blocked Akt and Erk phosphorylation in two gefitinib-sensitive NSCLC cell lines, further supporting our previous findings that persistent activity of the PI3K/Akt and/or Ras/Erk pathways is associated with gefitinib-resistance of NSCLC cell lines. Gefitinib-resistant NSCLC cell lines, showing EGFR-independent activity of the PI3K/Akt or Ras/Erk pathways, were treated with gefitinib in combination with specific inhibitors of mTOR, P13K, Ras, and MEK. Additive cytotoxicity was observed in A549 cells co-treated with gefitinib and the MEK inhibitor U0126 or the farnesyl transferase inhibitor SCH66336 and in H460 cells treated with gefitinib and the PI3K inhibitor LY294002, but not in H460 cells treated with gefitinib and rapamycin. These data suggest that combination treatment of NSCLC cells with gefitinib and specific inhibitors of the PI3K/Akt and Ras/Erk pathways may provide a successful strategy.
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PMID:Enhanced cytotoxicity induced by gefitinib and specific inhibitors of the Ras or phosphatidyl inositol-3 kinase pathways in non-small cell lung cancer cells. 1600 51

The EGF (epidermal growth factor) receptor-tyrosine kinase inhibitor ZD1839 (Gefitinib, 'Iressa') blocks the cell signaling pathways involved in cell proliferation, survival, and angiogenesis in various cancer cells. TNF-related death apoptosis inducing ligand (TRAIL) acts as an anticancer agent. We investigated the antitumor effects of ZD1839 alone or in combination with TRAIL against human esophageal squamous cell cancer (ESCC) lines. Although all ESCC cells expressed EGF receptor at a protein level, the effect of ZD1839 on cell growth did not correlate with the level of EGFR expression and phosphorylation of EGF receptor protein in ESCC lines. ZD1839 caused a dose-dependent growth arrest at G0-G1 phase associated with increased p27 expression. As TE8 cells are resistant to TRAIL, we tested whether ZD1839 combined with TRAIL induced apoptosis of TE8 cells via the inhibition of EGF receptor signaling by ZD1839. ZD1839 inhibited the phosphorylation of Akt, and enhanced TRAIL-induced apoptosis via activation of caspase-3 and caspase-9, and inactivation of Bcl-xL. Our results indicated that ZD1839 has anti-cancer properties against human esophageal cancer cells. ZD1839 also augmented the anti-cancer activity of TRAIL, even in TRAIL-resistant tumors. These results suggest that treatment with ZD1839 and TRAIL may have potential in the treatment of ESCC patients.
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PMID:ZD1839 (Gefitinib, 'Iressa'), an epidermal growth factor receptor-tyrosine kinase inhibitor, enhances the anti-cancer effects of TRAIL in human esophageal squamous cell carcinoma. 1602 8

Synovial sarcoma is a soft tissue malignancy with a poor prognosis; many patients will die from this disease within 10 years of diagnosis, despite treatment. Gene expression profiling and immunohistochemistry studies have identified oncogenes that are highly expressed in synovial sarcoma. Included in this group are receptor tyrosine kinases such as epidermal growth factor receptor, insulin-like growth factor receptor 1, fibroblast growth factor receptor 3, KIT, and HER2. Inhibitors of these growth-promoting receptors are likely to inhibit proliferation of synovial sarcoma; however, the effect of receptor tyrosine kinase inhibitors on synovial sarcoma is largely unknown. We assessed the ability of the following receptor tyrosine kinase inhibitors to halt proliferation and induce apoptosis in synovial sarcoma monolayer and three dimensional spheroid in vitro models: gefitinib (Iressa), NVP-AEW541, imatinib mesylate (Gleevec), SU5402, PRO-001, trastuzumab (Herceptin), and 17-allylamino-17-demethoxygeldanamycin (17-AAG). Gefitinib, NVP-AEW541, and imatinib inhibited proliferation only at relatively high concentrations, which are not clinically applicable. 17-AAG, which destabilizes multiple receptor tyrosine kinases and other oncoproteins through heat shock protein 90 inhibition, prevented proliferation and induced apoptosis in synovial sarcoma monolayer models at concentrations achievable in human serum. 17-AAG treatment was also associated with receptor tyrosine kinase degradation and induction of apoptosis in synovial sarcoma spheroid models. 17-AAG was more effective than doxorubicin, particularly in the spheroid models. Here we provide in vitro evidence that 17-AAG, a clinically applicable drug with known pharmacology and limited toxicity, inhibits synovial sarcoma proliferation by inducing apoptosis, and thus has potential as a systemic therapy for this disease.
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PMID:Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin prevents synovial sarcoma proliferation via apoptosis in in vitro models. 1606 82

Glioblastoma multiforme (GBM) is a highly malignant brain tumor with limited therapeutic options, a high recurrence rate and mortality. Standard therapy is maximal surgical resection and radiotherapy (RT). Recent data suggest combining temozolomide with RT is better than RT alone. Adjuvant chemotherapy has a modest impact on survival. For relapsed patients there is no standard therapy, but options include chemotherapeutic agents or new agents in development. One approach to improve outcome is using targeted agents that interfere with cell-surface receptors or intracellular signaling pathways. Between 40% and 50% of GBM tumors show HER1/EGFR dysregulation, and almost half co-express the constitutively active mutant receptor subtype EGFRvIII, which may contribute to the aggressive and refractory course of GBM. Numerous studies show a relationship between aberrant HER1/EGFR biology and tumorigenicity in GBM cells. Two available HER1/EGFR tyrosine kinase inhibitors (TKIs) are gefitinib (Iressa) and erlotinib (Tarceva); both show antitumor and radiosensitization effects in vitro and in animal models of GBM. Clinical trials in patients with GBM and other gliomas are ongoing. Preliminary and published results from trials of gefitinib in recurrent GBM show no increased time to progression or overall survival (OS) compared with historical controls. Studies with erlotinib show greater antitumor activity in patients with GBM than with gefitinib, although the impact of both agents on OS remains unclear. GBM treatment with HER1/EGFR TKIs alone or combined with other targeted therapies and conventional modalities deserve further investigation and refinement, as does our understanding of their mechanisms of action and the role of genetics.
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PMID:HER1/EGFR tyrosine kinase inhibitors for the treatment of glioblastoma multiforme. 1607 12

Studies of cell models and profiling of clinical breast cancer material to reveal the mechanisms of resistance to anti-oestrogen therapy, and to tamoxifen in particular, have reported that this phenomenon can be associated with increased expression and signalling through erbB Type 1 growth factor receptors, notably the epidermal growth factor receptor (EGFR) and HER2. Further molecular studies have revealed an intricate interlinking between such growth factor receptor pathways and oestrogen receptor (ER) signalling. Inhibition of receptor tyrosine kinase activity involved in the EGFR signalling cascade forms the basis for the use of EGFR specific tyrosine kinase inhibitors exemplified by gefitinib (ZD1839, Iressa) and erlotinib (OSI-774, Tarceva). Such agents have proved promising in pre-clinical studies and are currently in clinical trials in breast cancer, where gefitinib has been studied more extensively to date. Here, we present an overview of the current development of gefitinib in clinical breast cancer. This includes results from our clinical breast cancer trial 1839IL/0057 that demonstrate the efficacy of gefitinib within ER-positive, tamoxifen-resistant patients with locally advanced/metastatic disease, where parallel decreases in EGFR signal transduction and the Ki67 (MIB1) proliferation marker can be detected as predicted from model system studies. We also consider trials examining combination treatment with gefitinib and anti-hormonal strategies that will begin to address the clinically important question of whether gefitinib can delay/prevent onset of anti-hormone resistance.
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PMID:Overview of tyrosine kinase inhibitors in clinical breast cancer. 1611 90


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