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)

KIT and platelet-derived growth factor receptors (PDGFRs) play critical oncogenic roles in a broad spectrum of hematologic and solid tumors. These receptor tyrosine kinases, as well as ABL and BCR-ABL, are inhibited by imatinib. Tumors caused by chromosomal translocations that lead to overexpression of PDGFR ligand, resulting in continuous activation of wild-type PDGFRs, are likely to respond to imatinib, as are malignancies caused by gene amplification and overexpression of wild-type PDGFR or KIT receptors. Malignancies linked to chromosomal translocations that express PDGFR or KIT fusion protein-tyrosine kinases are also likely to respond to imatinib. Malignant cell responses to imatinib depend on whether any of these tyrosine kinase activities play essential roles in the oncogenesis of a given tumor, as well as the precise molecular mechanism underlying oncogenesis. For example, imatinib efficacy for malignancies arising from constitutively activating point mutations in tyrosine kinases depends on the exact location of the mutation in the kinase molecule.
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PMID:Role of KIT and platelet-derived growth factor receptors as oncoproteins. 1517 98

Solid malignancies often exhibit high interstitial fluid pressure (IFP), which causes poor uptake of anticancer drugs. While there are several mechanisms that regulate IFP in tumors, activation of platelet-derived growth factor receptor, which is expressed in various cell types within the tumor microenvironment, has been observed to play an important role in elevating IFP. In preclinical studies, treatment with imatinib, which inhibits both alpha- and beta-platelet-derived growth factor receptors, as well as KIT, ABL, ARG, and BCR-ABL tyrosine kinases, has been shown to decrease tumor IFP and concomitantly augment uptake of chemotherapeutic drugs, thereby enhancing the efficacy of chemotherapy. This review discusses preclinical studies showing the ability of imatinib to lower IFP and increase drug uptake within solid tumors, as well as the scientific rationale for clinical use of imatinib as combination therapy for chemotherapy.
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PMID:Increasing tumor uptake of anticancer drugs with imatinib. 1517

Internal tandem duplications (ITDs) of the FMS-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase are found in approximately 30% of patients with acute myelogenous leukemia (AML) and are associated with a poor prognosis. FLT3 ITD mutations result in constitutive kinase activation and are thought to be pathogenetically relevant, implicating FLT3 as a plausible therapeutic target. MLN518 (formerly CT53518) is a small molecule inhibitor of the FLT3, KIT, and platelet-derived growth-factor receptor (PDGFR) tyrosine kinases with significant activity in murine models of FLT3 ITD-positive leukemia. Given the importance of FLT3 and KIT for normal hematopoietic progenitor cells, we analyzed the effect of MLN518 on murine hematopoiesis under steady-state conditions, after chemotherapy-induced myelosuppression, and during bone marrow transplantation. In these assays, we show that MLN518 has mild toxicity toward normal hematopoiesis at concentrations that are effective in treating FLT3 ITD-positive leukemia in mice. We also demonstrate that MLN518 preferentially inhibits the growth of blast colonies from FLT3 ITD-positive compared with ITD-negative patients with AML, at concentrations that do not significantly affect colony formation by normal human progenitor cells. In analogy to imatinib mesylate in BCR-ABL-positive acute leukemia, MLN518-induced remissions may not be durable. Our studies provide the basis for integrating this compound into chemotherapy and transplantation protocols.
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PMID:Effects of MLN518, a dual FLT3 and KIT inhibitor, on normal and malignant hematopoiesis. 1524 81

Gastrointestinal stromal tumors (GIST) are defined as c-KIT-positive mesenchymal neoplasias located in the gastrointestinal tract and abdomen, most of which present an activating KIT mutation, a fundamental step in the development of disease. However, recent studies reported a small subgroup of KIT-negative GIST, in which platelet-derived growth factor receptor A, protein kinase C-tau, and FLJ10261 expression was detected. Imatinib (Gleevec, Novartis) is an orally administered competitive inhibitor of the tyrosine kinase domain of receptors such as KIT, ABL, and BCR-ABL fusion proteins, and the platelet-derived growth factor receptor. Phase I-III clinical trials have demonstrated the efficacy of imatinib in the treatment of metastatic GIST. However, the optimal dose and role of imatinib in an adjuvant or neoadjuvant setting have yet to be defined. Therefore, further studies investigating the mechanism of resistance to imatinib in patients with GIST are warranted.
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PMID:Current clinical management of gastrointestinal stromal tumors. 1527 Jun 63

Increasing knowledge of the mechanism of the initiation and progression of various cancers is the catalyst for developing new anticancer therapeutics that target specific molecules expressed in cancer cells. STI571 (imatinib mesylate) is an example of the successful development of a rationally designed and targeted agent. Its target is the constitutively active tyrosine kinase, BCR-ABL in chronic myelogenous leukemia (CML). Clinical studies with STI571 in CML demonstrated that many patients with advanced stage disease respond initially but then relapse. Drug resistance is associated with the reactivation of BCR-ABL signal transduction. Another targeted protein-tyrosine kinase inhibitor that was approved for clinical use is ZD1839 (Iressa). ZD1839 is an orally active and selective inhibitor for epidermal growth factor receptor (EGFR) tyrosine kinase. HER2 is overexpressed in 25-30% of breast cancers and associated with shorter time to relapse and lower survival rate. Specific targeting of these cancers can be accomplished with Herceptin directed against the extracellular domain of the HER2 protein. However, even in the selected group of patients with high levels of HER2, the response to Herceptin is limited in magnitude and duration. The mechanisms of the resistance to these targeted agents were reviewed.
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PMID:[The mechanisms of the resistance to molecular targeting agents]. 1528 47

Imatinib (Gleevec) exemplifies the successful development of a rationally designed, molecularly targeted therapy for the treatment of a specific cancer. This article reviews the identification of the BCR-ABL tyrosine kinase as a therapeutic target in chronic myeloid leukemia and the steps in the development of an agent to specifically inactivate this abnormality. The clinical trials results are reviewed along with a description of resistance mechanisms. As imatinib also inhibits the tyrosine kinase activity of KIT and the platelet-derived growth factor receptors, the extension of imatinib to malignancies driven by these kinases will be described. Issues related to clinical trials of molecularly targeted agents are discussed, including patient and dose selection. Last, the translation of this paradigm to other malignancies is explored.
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PMID:Imatinib as a paradigm of targeted therapies. 1532 87

KIT gain of function mutations play an important role in the pathogenesis of gastrointestinal stromal tumors (GISTs). Imatinib is a selective tyrosine kinase inhibitor of ABL, platelet-derived growth factor receptor (PDGFR), and KIT and represents a new paradigm of targeted therapy against GISTs. Here we report for the first time that, after imatinib treatment, an additional specific and novel KIT mutation occurs in GISTs as they develop resistance to the drug. We studied 12 GIST patients with initial near-complete response to imatinib. Seven harbored mutations in KIT exon 11, and 5 harbored mutations in exon 9. Within 31 months, six imatinib-resistant rapidly progressive peritoneal implants (metastatic foci) developed in five patients. Quiescent residual GISTs persisted in seven patients. All six rapidly progressive imatinib-resistant implants from five patients show an identical novel KIT missense mutation, 1982T-->C, that resulted in Val654Ala in KIT tyrosine kinase domain 1. This novel mutation has never been reported before, is not present in pre-imatinib or post-imatinib residual quiescent GISTs, and is strongly correlated with imatinib resistance. Allelic-specific sequencing data show that this new mutation occurs in the allele that harbors original activation mutation of KIT.
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PMID:A missense mutation in KIT kinase domain 1 correlates with imatinib resistance in gastrointestinal stromal tumors. 1534 66

Epidermal growth factor (EGF) and its cognate receptor (EGF-R) are often dysregulated in human neoplasia. Moreover, EGF-R-transformed cell lines have constitutive EGF-R activity, which makes elucidation of its effects difficult to determine. In the following studies, the effects of a novel conditionally activated form of EGF-R, v-ErbB:ER, on the morphological transformation of NIH-3T3 cells and the abrogation of hematopoietic cell cytokine dependence were investigated. The v-ErbB ES-4 oncogene was fused to the hormone binding domain of the estrogen receptor (ER). This construct, v-ErbB:ER, requires beta-estradiol or 4-OH tamoxifen for activation. v-ErbB:ER conditionally transformed NIH-3T3 cells and abrogated cytokine dependence of hematopoietic cells. Stimulation of v-ErbB:ER activity resulted in the activation of the phosphatidylinositol 3-kinase (PI3K)/Akt and Raf/MEK/ERK kinase cascades. To determine the importance of these signal transduction pathways, the conditionally transformed hematopoietic cells were treated with EGF-R, PI3K and MEK inhibitors. The EGF-R inhibitor AG1478 effectively inhibited MEK, ERK and Akt activation, and induced apoptosis when the cells were grown in response to v-ErbB:ER. Apoptosis was observed at 100- to 1000-fold lower concentrations of AG1478 when the cells were grown in response to v-ErbB:ER as opposed to IL-3. Furthermore, the parental, BCR-ABL- and Raf-transformed cells were only susceptible to the apoptosis-inducing effects of AG1478 at the highest concentrations demonstrating the specificity of these inhibitors. MEK or PI3K inhibitors suppressed ERK or Akt activation, respectively, and induced apoptosis in the v-ErbB:ER-responsive cells. However, MEK and PI3K inhibitors only induced apoptosis at 1000-fold higher concentrations than the EGFR inhibitor. This novel v-ErbB:ER construct and these conditionally transformed cell lines will be useful to further elucidate ErbB-mediated signal transduction and to determine the effectiveness of various inhibitors in targeting different aspects of EGF-R-mediated signal transduction and malignant transformation.
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PMID:Effects of a conditionally active v-ErbB and an EGF-R inhibitor on transformation of NIH-3T3 cells and abrogation of cytokine dependency of hematopoietic cells. 1536 36

Protein kinase inhibitors can be effective in treating selected cancers, but most suppress several kinases. Imatinib mesylate has been useful in the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia and B cell acute lymphoblastic leukemia through the inhibition of BCR-ABL tyrosine kinase activity. Imatinib mesylate has also been shown to inhibit KIT, ARG, and platelet-derived growth factor receptors alpha and beta, and potentially other tyrosine kinases. We have produced a mutant allele of BCR-ABL (T315A) that is uniquely inhibitable by the small molecule 4-amino-1-tert-butyl-3-(1-naphthyl)pyrazolo[3,4-d]pyrimidine and used it to demonstrate that sole suppression of BCR-ABL activity was insufficient to eliminate BCR-ABL(+) KIT(+)-expressing immature murine myeloid leukemic cells. In contrast, imatinib mesylate effectively eliminated BCR-ABL(+) KIT(+)-expressing leukemic cells. In the cellular context of mature myeloid cells and Pro/Pre B cells that do not express KIT, monospecific BCR-ABL inhibition was quantitatively as effective as imatinib mesylate in suppressing cell growth and inducing apoptosis. These results suggest that the therapeutic effectiveness of small molecule drugs such as imatinib mesylate could be due to the inhibitor's ability to suppress protein kinases in addition to the dominant target.
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PMID:Sole BCR-ABL inhibition is insufficient to eliminate all myeloproliferative disorder cell populations. 1550 16

Gastrointestinal stromal tumors (GISTs) are rare mesenchymal tumors of the gastrointestinal tract characterized by the expression of a receptor that activates tyrosine kinase called c-kit. Since malignant GISTs are resistant to conventional radiation therapy and chemotherapy, recurrent or malignant GIST has an extremely poor prognosis even after surgical resection. The development of a tyrosine kinase inhibitor, STI571 (imatinib mesylate, Glivec, Gleevec), which inhibits the BCR-ABL, PDGF-R alpha and c-kit receptors, has changed the management of unresectable malignant GIST and has improved the survival of patients with metastatic disease. We report a patient with GIST and diffused peritoneal metastases, whose tumor initially responded to STI571 and eventually became resistant. A 45-year-old woman underwent partial jejunostomy on September 3, 1998, under a diagnosis of submucosal tumor of the jejunum. Pathological examination of the primary tumor revealed a strong c-kit expression and GIST was diagnosed. The patient underwent an excision of peritoneal recurrences on October 31, 2000; April 17, 2001; and August 28, 2001. A treatment with STI571 (400 mg/day) was initiated on October 15, 2001, and she was free from peritoneal masses for 8 months after the fourth operation. However, the patient herself suspended the STI571 therapy for one month and multiple peritoneal metastases developed. Although the treatment with STI571 was restarted at 400 mg/day, the peritoneal masses did not respond this time. She died of liver, lung, and peritoneal metastases after the seventh cytoreductive operation on February 11, 2004. Several mechanisms of the resistance to STI571 have been identified. Amplification or an overexpression of KIT has been proposed to be involved in the resistance development. Several mutations of KIT were also correlated with the clinical outcome. Her tumors showed mutations in exons 9 or 11 of KIT, which had longer event-free and overall survival times than those tumors that had mutations of exons 13 or 17. In this case, an exon 11 mutation of KIT was initially noted. After the interruption of the treatment, an additional point mutation arose in exon 13 that caused a resistance to STI571. Currently STI571 is the first-line therapy for non-resectable GISTs, but a single-agent therapy often leads to tumor resistance. It is our hope that we will be able to design an alternative treatment to overcome such resistance.
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PMID:[A case of metastatic gastrointestinal stromal tumor developing a resistance to STI571 (imatinib mesylate)]. 1555 17


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