Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Modern molecular technology helped identify more than 10 protein tyrosine kinases related to myeloid malignancies, which allowed the development of small molecule inhibitors targeting deregulated protein tyrosine kinase activity. Protein tyrosine kinase deregulation can occur as a consequence of fusion gene formation because of chromosomal translocations, or as distinct gain-of-function point mutations. Although the tyrosine kinase inhibitor imatinib mesylate (Gleevec) targeting the ABL protein tyrosine kinase has revolutionized current chronic myeloid leukemia therapy, it became rapidly evident that overcoming the multiple cellular resistance mechanisms will be very challenging. To develop efficient therapeutic alternatives, one must understand the complex signal transduction mechanisms involved in transformation by deregulated protein tyrosine kinases. This article reviews the most recently identified molecular mechanisms involved in cell transformation by the BCR/ABL protein tyrosine kinase fusion and presents new members of the increasing family of deregulated protein tyrosine kinases involved in myeloproliferative disorders. In addition, the article discusses new, promising small molecule protein tyrosine kinase inhibitors and the molecular mechanism that may lead to resistance to these drugs. Finally, the article highlights putative alternative strategies that could be used to block signal transduction pathways of deregulated protein tyrosine kinase activity.
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PMID:Role of constitutively activated protein tyrosine kinases in malignant myeloproliferative disorders: an update. 1248 10

Chronic myelogenous leukemia (CML) is a myeloproliferative disease characterized by the BCR-ABL genetic translocation and constitutive activation of the Abl tyrosine kinase. Among members of the Signal Transducers and Activators of Transcription (STAT) family of transcription factors, Stat5 is activated by the Bcr-Abl kinase and is implicated in the pathogenesis of CML. We recently identified PD180970 as a new and highly potent inhibitor of Bcr-Abl kinase. In this study, we show that blocking Bcr-Abl kinase activity using PD180970 in the human K562 CML cell line resulted in inhibition of Stat5 DNA-binding activity with an IC(50) of 5 nM. Furthermore, abrogation of Abl kinase-mediated Stat5 activation suppressed cell proliferation and induced apoptosis in K562 cells, but not in the Bcr-Abl-negative myeloid cell lines, HEL 92.1.7 and HL-60. Dominant-negative Stat5 protein expressed from a vaccinia virus vector also induced apoptosis of K562 cells, consistent with earlier studies that demonstrated an essential role of Stat5 signaling in growth and survival of CML cells. RNA and protein analyses revealed several candidate target genes of Stat5, including Bcl-x, Mcl-1, c-Myc and cyclin D2, which were down-regulated after treatment with PD180970. In addition, PD180970 inhibited Stat5 DNA-binding activity in cultured primary leukemic cells derived from CML patients. To detect activated Stat5 in CML patient specimens, we developed an immunocytochemical assay that can be used as a molecular end-point assay to monitor inhibition of Bcr-Abl signaling. Moreover, PD180970 blocked Stat5 signaling and induced apoptosis of STI-571 (Gleevec, Imatinib)-resistant Bcr-Abl-positive cells. Together, these results suggest that the mechanism of action of PD180970 involves inhibition of Bcr-Abl-mediated Stat5 signaling and provide further evidence that compounds in this structural class may represent potential therapeutic agents for CML.
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PMID:Inhibition of Bcr-Abl kinase activity by PD180970 blocks constitutive activation of Stat5 and growth of CML cells. 1248 33

Acute myeloid leukemia (AML) remains the most common form of leukemia and the most common cause of leukemia death. Although conventional chemotherapy can cure between 25 and 45% of AML patients, most patients will either die of relapse or die from the complications associated with treatment. Thus, more specific and less toxic treatments for AML patients are needed. Recently, a small molecular inhibitor (STI571 or Gleevec) that targets the BCR-ABL gene was found to have a dramatic clinical effect in patients with chronic myelogenous leukemia (CML). These results have encouraged investigators to search for additional small molecular inhibitors and other targeted therapies that may be applicable to other forms of leukemia. In this review, we examine some of the signaling pathways that are aberrantly regulated in AML, focusing on the tyrosine kinase/RAS/MAP kinase and JAK/STAT pathways. After reviewing these two pathways, we explore some of the targeted therapies directed at these pathways that are under development for AML, many of which are already in clinical trials.
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PMID:Molecular targets in acute myelogenous leukemia. 1249 Feb 7

Cytoreductive therapy can ameliorate symptoms in chronic myeloid leukemia (CML) but only treatment beyond hematologic remission aiming to affect the leukemic clone can improve prognosis. Up to now bone marrow transplantation is the only established therapy with the potential to completely eliminate the BCR-ABL positive cell population. Interferon-alpha (IFN-alpha) as well as cytosine arabinoside (ARA-C), particularly in combination, have been shown to be effective in achieving cytogenetic remission in some patients. With Glivec (STI-571) there is now a drug available which can induce major cytogenetic response in more than half of the patients who have failed IFN-alpha treatment and thus possibly delay or prevent blast crisis. Recent reports, however, have shown that primitive, quiescent, Philadelphia-positive stem cells are insensitive to STI-571 in vitro. Such cells could be the basis of relapse after termination of Glivec-therapy.
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PMID:[Treatment of residual disease in chronic myeloid leukemia with STI-571 (Glivec)]. 1250 64

Fusion tyrosine kinases (FTKs) such as BCR/ABL, TEL/ABL, TEL/JAK2, TEL/PDGF beta R and NPM/ALK arise from reciprocal chromosomal translocations and cause acute and chronic myelogenous leukemias and non-Hodgkin's lymphoma. Murine hematopoietic growth factor dependent BaF3 cells and cells transformed by FTK (BaF3-FTK) were used to investigate the role of FTKs in response to DNA damage. FTK-transformed cells displayed resistance to genotoxic treatment including gamma-radiation and cytostatic agents such as idarubicin and MNNG. More FTK-transformed cells survived genotoxic treatment and were able to proliferate in comparison to parental non-transformed cells. Similar or higher levels of DNA damage was detected in gamma-irradiated in BaF3-FTK cells in comparison to BaF3 parental cells. Idarubicin induced different amounts of DNA damage in various BaF3-FTK cells. All BaF3-FTK cells treated with MNNG displayed significantly more DNA damage in comparison to BaF3 cells. Despite the extent of genotoxic effect BaF3-FTK cells were often able to repair damaged DNA more efficiently that the non-transformed counterparts. Inhibition of BCR/ABL kinase activity by STI571 (Gleevec, inatinib mesylate) abrogated the resistance to genotoxic treatment and inhibited DNA repair mechanisms. We hypothesize that facilitation of the DNA repair in FTK-positive cells may contribute to their resistance to genotoxic treatment.
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PMID:Fusion oncogenic tyrosine kinases alter DNA damage and repair after genotoxic treatment: role in drug resistance? 1253 80

The onset of accelerated phase or blast crisis of chronic myelocytic leukemia (CML) is usually associated with the acquisition of new chromosome abnormalities in addition to the t(9;22)(q34;q11) that is characteristic of the chronic phase CML. We describe the cytogenetic and molecular genetic findings in two cases of myelocytic blast crisis of CML, one occurring 6 months after commencing treatment with the ABL-specific tyrosine kinase inhibitor imatinib mesylate (STI571, Glivec, or Gleevec) and the second treated with imatinib mesylate for established blast crisis. In both cases, multiple secondary cytogenetic abnormalities were observed at transformation, with homogeneously staining regions that were shown to contain BCR/ABL amplification by fluorescence in situ hybridization appearing after imatinib mesylate administration. BCR/ABL amplification is emerging as an important mechanism of acquired resistance to imatinib mesylate.
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PMID:BCR/ABL amplification in chronic myelocytic leukemia blast crisis following imatinib mesylate administration. 1254 54

Because conventional chemotherapy is not specific for cancer cells leading to toxic side effects there is a need for novel agents with high grade antitumor specificity. The major prerequisite to develop such drugs is to understand the targets that these agents should attack. In recent years a number of promising new anticancer drugs have been developed which target intracellular pathways or extracellular cell molecules. The clinically most effective compounds function as tyrosine kinase inhibitors. In the past, various tyrosine kinase receptors have been identified as regulators of tumor or tumor vessel growth. Having shown their expression characteristics in different tumor entities, specific inhibitors of the ATP binding sites of these receptors or antibodies were developed and entered clinical trials. The pathognomonic role of the tyrosine kinase defines the way of action of the inhibiting drug, whereas the amount of expression in tumor tissue defines the rationale to use the inhibitor to treat a specific protein. The future will define indications for such drugs by tumor kinase profiles instead of tumor entities. Gleevec, inhibiting the BCR-ABL tyrosine kinase; Iressa, inhibiting the EGF-receptor tyrosine kinase; Herceptin, inhibiting the Her2/neu tyrosine kinase and PTK787/ZK222584, inhibiting the VEGF-receptor tyrosine kinase will be discussed as representatives of selective tyrosine kinase inhibitors whereas ZD6474 and SU6668 will be discussed as representatives of multitarget tyrosine kinase inhibitors.
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PMID:Receptor tyrosine kinases: the main targets for new anticancer therapy. 1255 64

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

Imatinib mesylate (STI571, Gleevec, Glivec, a selective inhibitor of the BCR-ABL tyrosine kinase causative of chronic myeloid leukemia (CML), represents the paradigm of how a better understanding of the pathogenetic mechanisms of a neoplastic disease can lead to the development of a targeted molecular therapy. Phase II clinical trials have shown marked therapeutic activity of imatinib in all evolutive phases of CML, but notably in the chronic phase, where it induces complete hematological responses in almost 100% of patients resistant or intolerant to interferon, with a major cytogenetic response rate of 60%, including 41% complete cytogenetic responses. The preliminary results of an ongoing phase III multicenter randomized study comparing imatinib with interferon plus cytarabine as first-line treatment for CML favor imatinib in terms of efficacy and safety. If confirmed with longer follow-up,these results would establish imatinib as the choice therapy for the majority of CML patients, with allogeneic transplantation being restricted as initial therapy only to younger patients with a family donor. Longer follow-up will answer some questions, such as those on long-term safety, durability of the responses, whether these will translate into a survival prolongation and the possibility of molecular responses. In addition, further information on the mechanisms involved in the primary and acquired resistance to imatinib is needed. Besides the Bcr-Abl protein, the drug is also active against other tyrosine kinases, such as Abl, the stem-cell factor receptor (c-kit) and the platelet-derived growth factor receptor, whose inhibition might have potential implications for the treatment of several malignancies. In this sense, it must be pointed out that imatinib has shown a remarkable activity in gastrointestinal stromal tumors.
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PMID:Imatinib mesylate (Gleevec, Glivec): a new therapy for chronic myeloid leukemia and other malignancies. 1258 48

Until recently, progress in the treatment of patients with Ph(+) acute lymphoblastic leukaemia (ALL) has been limited, and long-term survival, even with high-dose intensified chemotherapy, is rare. Allogeneic stem cell transplantation is potentially curative, but treatment-related mortality and rate of disease recurrence are substantial. With the advent of the ABL-selective tyrosine kinase inhibitor STI571 (imatinib mesylate, Glivec), it has become apparent that the understanding of crucial leukaemogenic pathways at the molecular level can lead to the development of specific and selective agents. In recent clinical trials, imatinib has demonstrated significant anti-leukaemic efficacy in patients with advanced Ph(+) ALL, in conjunction with a remarkably favourable safety profile. Clinical resistance to imatinib develops rapidly, highlighting the limitations of using imatinib as a single agent; however, the value of imatinib as an element of treatment has become apparent. Resistance mechanisms have already been identified that will enable the development of rational strategies to prevent or overcome resistance. On the basis of available clinical results, combinations of imatinib with established anti-leukaemic agents, as well as with novel, molecularly targeted treatment modalities, will need to be evaluated in advanced Ph(+) ALL. Incorporation of imatinib in the first-line treatment of de novo Ph(+) ALL and in the setting of minimal residual disease is a promising therapeutic approach which is currently being studied in clinical trials. Better understanding of targeted therapies, including strategies based on recruitment of host immune functions, as well as the prudent use of active chemotherapy agents, may eventually improve the outlook for patients with Ph(+) ALL.
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PMID:Imatinib in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukaemia: current status and evolving concepts. 1261 75


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