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, an inhibitor of tyrosine kinases including BCR-ABL and KIT, inhibits the growth inhibition of small cell lung cancer (SCLC) cell lines in vitro. However, clinical trials of imatinib mesylate alone in patients with SCLC resulted in unsatisfactory outcomes. Vitamin K2 (menaquinone-4: VK2) induces apoptosis and differentiation in leukemia cells. We recently reported that VK2 also induces apoptosis in lung cancer cell lines. In the present study, we focused on the in vitro combined effects of imatinib mesylate plus VK2 on SCLC cell lines such as LU-139, LU-130, NCI-H69 and NCI-H128. Treatment with imatinib mesylate and VK2 for 96 h resulted in suppression of cell growth in a dose-dependent manner in all cell lines tested. The 50% inhibitory concentration (IC50) for imatinib mesylate ranged from 17-29 microM, whereas the IC50 for VK2 ranged from 16-64 microM. Combined treatment of imatinib mesylate plus VK2 resulted in pronounced inhibition of cell growth. The morphologic features of cells treated with imatinib mesylate and VK2 were typical of apoptosis. Since VK2 is a safe medicine without prominent adverse effects, treatment of patients with SCLC could derive therapeutic benefits from a combination of imatinib mesylate and VK2.
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PMID:Combination of vitamin K2 plus imatinib mesylate enhances induction of apoptosis in small cell lung cancer cell lines. 1558 22

The BCR/ABL fusion tyrosine kinase activates various intracellular signaling pathways, thus causing chronic myeloid leukemia (CML). Here we demonstrate that the inducible expression of BCR/ABL in a murine hematopoietic cell line, TonB210, leads to the activation of the Ras family small GTPase Rap1, which is inhibited by the ABL kinase inhibitor imatinib. The Rap1 activity in a CML cell line, K562, was also inhibited by imatinib. Inhibition of Rap1 activation by a dominant negative mutant of Rap1, Rap1-N17, or SPA-1 inhibited the BCR/ABL-induced activation of Elk-1. BCR/ABL also activated in a kinase activity-dependent manner the B-Raf kinase, which is an effector molecule of Rap1 and a potent activator of the MEK/Erk/Elk-1 signaling pathway. Together, these data suggest that, in addition to the well-established Ras/Raf-1 pathway, BCR/ABL activates the alternative signaling pathway involving Rap1 and B-Raf to activate Erk, which may play important roles in leukemogenesis.
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PMID:BCR/ABL activates Rap1 and B-Raf to stimulate the MEK/Erk signaling pathway in hematopoietic cells. 1559 48

Previous work has demonstrated that chromosome 11 is trisomic or shows a duplicated region encompassing the E1/E2 band of chromosome 11 in 90% of v-abl/myc-induced plasmacytomas (Wiener et al. 1995). In the present report, we have studied BALB/c PreB lymphocytes that were immortalized by v-abl and stably transfected with a conditional MycER vector (Mai et al. 1999). These cells, termed PreB ABL/MYC, showed changes in the E1/E2 bands of chromosome 11 that are similar to those reported previously for v-abl/myc-induced plasmacytomas. This was shown by the use of chromosome painting, SKY, FISH and mBAND. Our findings suggest that the Pre-B ABL/MYC cells may be used to analyse the genetic changes affecting chromosome 11 that are associated with v-abl/myc-dependent tumorigenesis in mouse B cells.
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PMID:Rearrangements of the telomeric region of mouse chromosome 11 in Pre-B ABL/MYC cells revealed by mBANDing, spectral karyotyping, and fluorescence in-situ hybridization with a subtelomeric probe. 1570 16

Imatinib mesylate is a potent and specific tyrosine kinase inhibitor against c-ABL, BCR-ABL, and c-KIT, and has been demonstrated to be highly active in chronic myeloid leukemia and gastrointestinal stromal tumors. We examined the antifibrotic effects of imatinib using a bleomycin-induced lung fibrosis model in mice because imatinib also inhibits tyrosine kinase of platelet-derived growth factor receptors (PDGFRs). Imatinib inhibited the growth of primary murine lung fibroblasts and the autophosphorylation of PDGFR-beta induced by PDGF. Administration of imatinib significantly prevented bleomycin-induced pulmonary fibrosis in mice, partly by reducing the number of mesenchymal cells incorporating bromodeoxyuridine. Analysis of bronchoalveolar lavage cells demonstrated that imatinib did not suppress early inflammation on Days 7 and 14 caused by bleomycin. These results suggest that imatinib has the potential to prevent pulmonary fibrosis by inhibiting the proliferation of mesenchymal cells, and that imatinib might be useful for the treatment of pulmonary fibrosis in humans.
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PMID:Imatinib as a novel antifibrotic agent in bleomycin-induced pulmonary fibrosis in mice. 1573 62

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

Targeted molecular therapeutics are tailored toward the genetic abnormalities that cause tumor progression. Modulation of certain signaling pathways that are aberrant in cancer cells has the potential to provide an effective, nontoxic approach to therapy in a broad range of cancers. Agents targeting BCR-ABL (imatinib mesylate [formerly known as STI-571], Gleevec; Novartis Pharmaceuticals Corp, East Hanover, NJ), retinoid receptor fusion proteins (all-trans retinoic acid), ErbB-2 or HER2/neu (trastuzumab, Herceptin; Genentech, Inc, South San Francisco, CA), epidermal growth factor receptor (IMC-C225 and ZD1839), and the phosphatidylinositol 3-kinase pathway (CCI-779) have all induced remarkable, nontoxic responses in a subset of patients with cancer and abnormalities in the corresponding signal transduction cascades. To achieve successful individualized therapy, the specific components within the aberrant signaling pathways that are driving the pathophysiology of the tumors must be identified in each patient. Molecular diagnostics can identify patients in whom the target is aberrant; linking molecular diagnostics with effective molecular therapeutics will be necessary to translate these concepts into approaches that will alter the outcome for patients with cancer. In addition, intermediary markers and/or molecular imaging techniques must be used to identify the biologically relevant dose that is sufficient to inhibit the target of interest. This review focuses on the P13K pathway, and novel molecules targeting this pathway, to illustrate the questions and challenges underlying the implementation of molecular therapeutics in breast and ovarian cancer.
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PMID:Mammalian target of rapamycin. 1579 39

Over the past 5 years, small molecule tyrosine kinase inhibitors have been successfully introduced as new cancer therapeutics. The pioneering work with the ABL inhibitor imatinib (Glivec, Gleevec) was rapidly extended to other types of leukemias as well as solid tumors, which stimulated the development of a variety of new tyrosine kinase inhibitors. Unfortunately, oncogenic tyrosine kinases seem to have little problem to develop resistance to these inhibitors, and there is good evidence that this is not limited to imatinib, but also occurs with other inhibitors, such as FLT3 and EGFR inhibitors. Based on studies with imatinib, mutation and amplification of the target kinase seem to be the most important mechanisms for the development of resistance, but these mechanisms alone cannot explain all cases of resistance. A better understanding of the resistance mechanisms will be required to design improved treatment strategies in the future. In this review, we summarize the current insights in the different mechanisms of resistance to small molecule tyrosine kinase inhibitors, and discuss future improvements that might limit or even overcome resistance.
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PMID:Resistance to tyrosine kinase inhibitors: calling on extra forces. 1586 1

Conventional chemotherapeutic drugs are ineffective in treatment of gastrointestinal stromal tumors (GISTs). Imatinib (STI571, Gleevec, Glivec; Novartis Pharmaceuticals, East Hanover, NJ), a selective inhibitor of KIT, ABL, BCR-ABL, PDGFRA, and PDGFRB, represents a new paradigm of targeted cancer therapy and has revolutionized the treatment of patients with chronic myelogenous leukemia and GISTs. Unfortunately, imatinib resistance has emerged. The reported mechanism of imatinib resistance in GISTs involves missense mutation in the kinase domain of KIT, including Thr670Ile, Tyr823Asp, and Val654Ala. The established mechanisms and potential mechanisms of imatinib resistance in GISTs, the imaging studies indicative of early development of imatinib resistance, and the management of imatinib-resistant GISTs are discussed.
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PMID:Imatinib resistance in gastrointestinal stromal tumors. 1594 89

Oncogenic conversion of receptor protein tyrosine kinases (RTK) is a frequent feature of malignant cells. This knowledge has fostered efforts to develop target-specific low molecular weight therapeutics able to obstruct RTK signalling. The clinical efficacy of the ABL- and KIT-inhibitors are paradigmatic of the power of this approach. Here, we focus on small-molecule inhibitors for RTKs involved in human cancer. In particular, we examine the KIT, MET and RET receptors that are targeted by genetic alterations in both sporadic and familial human tumours.
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PMID:Receptor tyrosine kinases as targets for anticancer therapeutics. 1602 46

To realize the full potential of targeted protein kinase inhibitors for the treatment of cancer, it is important to address the emergence of drug resistance in treated patients. Mutant forms of BCR-ABL, KIT, and the EGF receptor (EGFR) have been found that confer resistance to the drugs imatinib, gefitinib, and erlotinib. The mutations weaken or prevent drug binding, and interestingly, one of the most common sites of mutation in all three kinases is a highly conserved "gatekeeper" threonine residue near the kinase active site. We have identified existing clinical compounds that bind and inhibit drug-resistant mutant variants of ABL, KIT, and EGFR. We found that the Aurora kinase inhibitor VX-680 and the p38 inhibitor BIRB-796 inhibit the imatinib- and BMS-354825-resistant ABL(T315I) kinase. The KIT/FLT3 inhibitor SU-11248 potently inhibits the imatinib-resistant KIT(V559D/T670I) kinase, consistent with the clinical efficacy of SU-11248 against imatinib-resistant gastrointestinal tumors, and the EGFR inhibitors EKB-569 and CI-1033, but not GW-572016 and ZD-6474, potently inhibit the gefitinib- and erlotinib-resistant EGFR(L858R/T790M) kinase. EKB-569 and CI-1033 are already in clinical trials, and our results suggest that they should be considered for testing in the treatment of gefitinib/erlotinib-resistant non-small cell lung cancer. The results highlight the strategy of screening existing clinical compounds against newly identified drug-resistant mutant variants to find compounds that may serve as starting points for the development of next-generation drugs, or that could be used directly to treat patients that have acquired resistance to first-generation targeted therapy.
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PMID:Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases. 1604 38


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