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:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The twenty-first century is beginning with a sharp turn in the field of cancer therapy. Molecular targeted therapies against specific oncogenic events are now possible. The BCR-ABL story represents a notable example of how research from the fields of cytogenetics, retroviral oncology, protein phosphorylation, and small molecule chemical inhibitors can lead to the development of a successful molecular targeted therapy. Imatinib mesylate (Gleevec, STI571, or CP57148B) is a direct inhibitor of ABL (ABL1), ARG (ABL2), KIT, and PDGFR tyrosine kinases. This drug has had a major impact on the treatment of chronic myelogenous leukemia (CML) as well as other blood neoplasias and solid tumors with etiologies based on activation of these tyrosine kinases. Analysis of CML patients resistant to BCR-ABL suppression by Imatinib mesylate coupled with the crystallographic structure of ABL complexed to this inhibitor have shown how structural mutations in ABL can circumvent an otherwise potent anticancer drug. The successes and limitations of Imatinib mesylate hold general lessons for the development of alternative molecular targeted therapies in oncology.
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PMID:The BCR-ABL story: bench to bedside and back. 1503 71

We report a case of BCR-ABL-negative atypical chronic myeloid leukemia (CML) with translocation t(4;22) (q12;q11.2) juxtaposing the breakpoint cluster region (BCR) and platelet-derived growth factor receptor-alpha (PDGFRA) genes. The patient was a 57-year-old man with a history of stage IV diffuse large B-cell lymphoma, status post-6 cycles of combination chemotherapy in 1999, who presented in August 2002 with enlarged lymph nodes, anemia, and marked leukocytosis (50 x 10(9) g/dL) consistent with a myeloproliferative disorder (MPD). A bone marrow biopsy showed granulocytic hyperplasia, neutrophilia, and mild eosinophilia. Initial cytogenetic evaluation by interphase FISH for BCR-ABL, to rule out a translocation 9;22, showed a variant signal pattern consistent with rearrangement of BCR at 22q11.2, but not ABL at 9q34. Analysis of the patient's cDNA by polymerase chain reaction (PCR) for BCR-ABL was negative. Cytogenetic analysis showed an abnormal karyotype with rearrangement of chromosomes 4 and 22. PCR amplification and subsequent sequence analysis demonstrated an in-frame 5'-BCR/3'-PDGFRA fusion in the patient's cDNA. PDGFRA encodes a receptor tyrosine kinase and shares structural and organizational homology with the KIT and CSf1R receptor genes. However, although the incidence of MPD involving translocations of PDGFRB has been well established, to our knowledge there are only two previous reports describing a BCR-PDGFRA fusion gene, in 3 patients diagnosed with atypical CML. Here, we report the molecular and cytogenetic characterization of a patient with BCR-PDGFRA-positive MPD who had a complete hematologic response after treatment with imatinib mesylate.
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PMID:Molecular and cytogenetic characterization of a novel translocation t(4;22) involving the breakpoint cluster region and platelet-derived growth factor receptor-alpha genes in a patient with atypical chronic myeloid leukemia. 1503 67

Imatinib mesylate is remarkably effective in treating chronic myeloid leukemia and metastatic gastrointestinal stromal tumors. Meanwhile, anaplastic thyroid carcinoma (ATC) remains a fatal malignancy for which there are currently no effective curative interventions. In chronic myeloid leukemia and gastrointestinal stromal tumors, imatinib inhibits the constitutive tyrosine kinase activity of BCR-ABL and c-KIT, respectively. Reports suggest that imatinib may also be effective against ABL and platelet-derived growth factor receptor kinase-dependent pathological conditions. These mechanisms provide a wide scope of possible clinical applications for the drug. Potentially, diseases instigated by constitutive kinase activity that can be inhibited with imatinib should be treatable with this drug. We evaluated the effects of imatinib on the viability, cycling, and tyrosine phosphorylation of ATC cells in vitro. Our data indicate that imatinib has negligible antineoplastic activity against ATC cell lines within established therapeutically useful concentrations. No constitutive kinase activity was detected in these cell lines that could be exploited as a therapeutic target by imatinib. We conclude that imatinib mesylate monotherapy would not be effective in ATC patients. Current preclinical data do not warrant future clinical studies of imatinib monotherapy for ATC.
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PMID:Imatinib mesylate (gleevec; STI571) monotherapy is ineffective in suppressing human anaplastic thyroid carcinoma cell growth in vitro. 1512 30

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

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

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


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