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)

Identification of the key roles of protein kinases in signaling pathways leading to development of cancer has caused pharmacological interest to concentrate extensively on targeted therapies as a more specific and effective way for blockade of cancer progression. This review will mainly focus on inhibitors targeting these key components of cellular signaling by employing a technology-based point of view with respect to ATP- and non-ATP-competitive small molecule inhibitors and monoclonal antibodies of selected protein kinases, particularly, mammalian target of rapamycin (mTOR), BCR-ABL, MEK, p38 MAPK, EGFR PDGFR, VEGFR, HER2 and Raf. Inhibitors of the heat shock protein Hsp90 are also included in a separate section, as this protein plays an essential role for the maturation/proper activation of cancer-related protein kinases. In the following review, the molecular details of the mode of action of these inhibitors as well as the emergence of drug resistance encountered in several cases are discussed in light of the structural, molecular and clinical studies conducted so far.
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PMID:Protein kinases as drug targets in cancer. 1710 May 68

STI571 (imatinib; Gleevec) was developed to specifically target the tyrosine kinase activity of the Bcr-Abl protein in Philadelphia chromosome-positive chronic myeloid leukemia (CML). It also inhibits the activity of c-Kit and PDGFR. It is the first-line drug for newly diagnosed CML, with remarkable efficacy to patients in the chronic phase of this cancer. However, CML patients in the accelerated phase or blast crisis often relapse due to drug resistance. STI571 fails to eradicate leukemic stem cells, and BCR-ABL(+). cells remain detectable in the majority of patients. The necessity for alternative or additional treatment for STI571-resistant leukemia resulted in the development of a second generation of drugs for targeted therapies. In this review a literature overview of the alternative inhibitors which were designed to override STI571 resistance and decrease the aberrant kinase activity of Bcr-Abl protein with higher efficiency is presented.
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PMID:[Novel inhibitors of Bcr-Abl]. 1724 19

Ewing sarcoma is a highly malignant tumor of bone preferentially arising in children and young adults. Its 5-year survival rate is only 50% despite the use of multimodal therapeutic approaches, requiring a search for new therapeutic targets and the development of novel therapeutic modalities. KIT and PDGFRs are type III receptor tyrosine kinases, and activating mutations in c-kit (which encodes KIT) and PDGFRs have been reported as oncogenic events in many malignancies. Imatinib is a selective inhibitor of KIT, PDGFR, and ABL tyrosine kinase activity and exerts different anti-tumor effects according to the regions of mutations in c-kit and PDGFR genes. Thus, we evaluated the immunohistochemical expression of KIT protein and the mutational status of exons 9, 11, 13, and 17 of the c-kit gene, exons 12 and 18 of the PDGFRA gene, and exon 12 of the PDGFRB gene in 71 formalin-fixed, paraffin-embedded Ewing sarcomas to increase our understanding of the potential, if any, of imatinib treatment for this malignancy. Of the 71 samples, 27 (38%) were immunohistochemically positive for KIT; however, activating mutations in c-kit were found in only 2 of 71 Ewing sarcomas (2.6%) within exon 9. No activating mutations in the PDGFRA and PDGFRB genes were found, but pleomorphism was identified in exon 18 of the PDGFRA gene. Our results for KIT protein expression agree with those of previous studies. This is the largest series of c-kit mutational analysis in Ewing sarcoma to date, and the results definitively show that c-kit activating mutations are not coincident with KIT protein expression in Ewing sarcoma in most samples. These findings imply other mechanisms for KIT activity and leave open the question of whether imatinib would be efficacious in the treatment of Ewing sarcoma.
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PMID:Protein expression of KIT and gene mutation of c-kit and PDGFRs in Ewing sarcomas. 1729 67

The FIP1-like-1 (FIP1L1)-platelet-derived growth factor receptor-alpha (FIP1L1-PDGFR-alpha) fusion kinase causes hypereosinophilic syndrome (HES) in a defined subset of patients. Imatinib mesylate is a potent inhibitor of ABL but also of PDGFR-alpha, and has been associated with durable hematologic responses in patients with HES. However, development of mutations in the tyrosine kinase domain may hamper the activity of tyrosine kinase inhibitors (TKIs), which suggests that novel agents are warranted to prevent or overcome resistance. We evaluated the efficacy of the novel TKI EXEL-0862 in FIP1L1-PDGFR-alpha-expressing cell lines and in cells from a patient with HES harboring the FIP1L1-PDGFR-alpha gene. EXEL-0862 inhibited the proliferation of EOL-1 and imatinib-resistant T674I FIP1L1-PDGFR-alpha-expressing cells and resulted in potent inhibition of the phosphorylation of PDGFR-alpha and downstream proteins STAT3 and Erk1/2, both in vitro and ex vivo. Moreover, EXEL-0862 induced apoptotic death in EOL-1 cells and imatinib-resistant T674I FIP1L1-PDGFR-alpha-expressing cells, and resulted in significant downregulation of the antiapoptotic protein Mcl-1 through a caspase-dependent mechanism. Our data establish EXEL-0862 as a solid candidate for the targeted treatment of patients with FIP1L1-PDGFR-alpha-positive HES.
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PMID:The novel tyrosine kinase inhibitor EXEL-0862 induces apoptosis in human FIP1L1-PDGFR-alpha-expressing cells through caspase-3-mediated cleavage of Mcl-1. 1749 75

The term chronic myeloproliferative disorders was originally used by Damashek to describe the link amongst a group of acquired blood diseases. Recent molecular genetic analysis has provided a scientific basis for this observation. Underlying myeloproliferative disorders are acquired abnormalities of tyrosine kinase genes. These may be chromosomal translocations resulting in the creation of a fusion kinase gene, examples of which include ABL, FGFR, and PDGFR as seen in disorders CML, 8p11 myeloproliferative syndrome, atypical CML and chronic eosinophilic leukaemia. The second group of tyrosine kinase abnormalities are point mutations in JAK2, a cytosolic TK. This abnormality is seen in 30-97% of cases of MPD with the phenotype PV, ET or CIMF.
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PMID:Chronic myeloproliferative disorders: the role of tyrosine kinases in pathogenesis, diagnosis and therapy. 1758 79

Persistent T cell activation is a common finding in anti-neutrophil cytoplasmic autoantibodies (ANCA)-associated systemic vasculitis (AAV) patients. Because imatinib, a selective inhibitor of the ABL, ARG, PDGFR and c-KIT tyrosine kinases, inhibits T cell activation, this study was conducted to evaluate the potential use of imatinib for the treatment AAV patients refractory to conventional therapy. In particular, we investigated the inhibition of T cell activation by this drug and its efficacy on activated T cells from anti-neutrophil cytoplasmic autoantibodies (ANCA)-associated systemic vasculitides (AASV) patients. T cell stimulation has been induced by anti-CD3/anti-CD28 antibodies or by phorbol myristate acetate (PMA)/ionomycin. T cell proliferation was analysed by tritiumthymidine incorporation. Cell cycle progression was determined by propidium iodide staining using fluorescence activated cell sorter (FACS) analysis and by RNAse protection assay (RPA). Cytokine levels were assessed by enzyme-linked immunosorbent assay. T cell proliferation was inhibited significantly by imatinib, due most probably to cell cycle arrest in the G1-phase. This was paralleled by inhibition in the expression of cyclin-dependent kinases 1 and 2 mRNA. The expression of CD25 in naive and memory T cells was decreased significantly by imatinib in activated T cells. Similarly, conversion from naive to memory T cells after T cell activation was impaired by imatinib. Imatinib did not influence interleukin-2 and tumour necrosis factor-alpha production but increased interferon-gamma production. These observed effects of imatinib were similar in T cells from AASV patients and from healthy individuals. Imatinib might be an alternative therapeutical option for AASV patients refractory to conventional therapy.
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PMID:Imatinib mesylate, a new kid on the block for the treatment of anti-neutrophil cytoplasmic autoantibodies-associated vasculitis? 1819 Jun 1

Schwannomas are tumors of the nervous system that occur sporadically and in patients with the cancer predisposition syndrome neurofibromatosis type 2 (NF2). Schwannomas and all NF2-related tumors are caused by loss of the tumor suppressor merlin. Using our human in vitro model for schwannoma, we analyzed extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT signaling pathways, their upstream growth factor receptors, and their role in schwannoma cell proliferation and adhesion to find new systemic therapies for these tumors that, to date, are very difficult to treat. We show here that human primary schwannoma cells show an enhanced basal Raf/mitogen-activated protein/ERK kinase/ERK1/2 pathway activity compared with healthy Schwann cells. Due to a strong and prolonged activation of platelet-derived growth factor receptor beta (PDGFRbeta), which is highly overexpressed, ERK1/2 and AKT activation was further increased in schwannoma, leading to increased proliferation. Using specific inhibitors, we discovered that ERK1/2 activation involves the integrin/focal adhesion kinase/Src/Ras signaling cascades and PDGFRbeta-mediated ERK1/2 activation is triggered through the phosphatidylinositol 3-kinase/protein kinase C/Src/c-Raf pathway. Due to the complexity of signals leading to schwannoma cell proliferation, potential new therapeutic agents should target several signaling pathways. The PDGFR and c-Raf inhibitor sorafenib (BAY 43-9006; Bayer Pharmaceuticals), currently approved for treatment of advanced renal cell cancer, inhibits both basal and PDGFRbeta-mediated ERK1/2 and AKT activity and decreases cell proliferation in human schwannoma cells, suggesting that this drug constitutes a promising tool to treat schwannomas. We conclude that our schwannoma in vitro model can be used to screen for new therapeutic targets in general and that sorafenib is possible candidate for future clinical trials.
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PMID:Dissecting and targeting the growth factor-dependent and growth factor-independent extracellular signal-regulated kinase pathway in human schwannoma. 1859 24

Malignant solitary fibrous tumor (MSFT) of the pleura is a rare neoplasm, with unpredictable biologic behavior and a low sensitivity to chemotherapy. To the authors' knowledge, no other effective medical treatment is available for this disease. Imatinib mesylate is a tyrosine kinase inhibitor targeting the platelet-derived growth factor (PDGFR-alpha and PDGFR-beta), the BCR-ABL, and c-KIT receptors. We report the first evidence of the activity of imatinib in a symptomatic patient with a chemo- and radio-resistant advanced MSFT, who obtained a 21-months lasting major clinical benefit with a consistent reduction in tumor metabolism. Immunostaining of tumor cells demonstrated the positivity for PDGFR-alpha and PDGFR-beta and the absence of c-KIT over-expression, in the absence of c-KIT and PDGRFR mutations; all the cells strongly and diffusely expressed the ligand PDGF A in the cytoplasm. This profile suggests that the observed tumor response was mediated through the inhibition of the tyrosine kinase activity of PDGFR. Treatment with imatinib should be considered for patients with recurrent or unresectable MSFTs with PDGFR expression.
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PMID:Brief report: activity of imatinib in a patient with platelet-derived-growth-factor receptor positive malignant solitary fibrous tumor of the pleura. 1867 Mar 17

NSCLC cells with a mesenchymal phenotype have shown a marked reduction in sensitivity to EGFR inhibitors, though the molecular rationale has remained obscure. Here we find that in mesenchymal-like tumor cells both tyrosine phosphorylation of EGFR, ErbB2, and ErbB3 signaling networks and expression of EGFR family ligands were decreased. While chronic activation of EGFR can promote an EMT-like transition, once having occurred EGFR family signaling was attenuated. We investigated the mechanisms by which mesenchymal-like cells bypass EGFR signaling and acquire alternative routes of proliferative and survival signaling. Mesenchymal-like NSCLC cells exhibit aberrant PDGFR and FGFR expression and autocrine signaling through these receptors can activate the MEK-ERK and PI3K pathways. Selective pharmacological inhibition of PDGFR or FGFR receptor tyrosine kinases reduced cell proliferation in mesenchymal-like but not epithelial NSCLC cell lines. A metastable, reversible EMT-like transition in the NSCLC line H358 was achieved by exogenous TGFbeta, which served as a model EMT system. The H358/TGFbeta cells showed many of the attributes of established mesenchymal-like NSCLC cells including a loss of cell-cell junctions, a loss of EGF-family ligand expression, a loss of ErbB3 expression, increased EGFR-independent Mek-Erk pathway activation and reduced sensitivity to EGFR inhibition. Notably an EMT-dependent acquisition of PDGFR, FGFR and TGFbeta receptors in H358/TGFbeta cells was also observed. In H358/TGFbeta cells both PDGFR and FGFR showed functional ligand stimulation of their intrinsic tyrosine kinase activities. The findings of kinase switching and acquired PDGFR and FGFR signaling suggest investigation of new inhibitor combinations to target NSCLC metastases.
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PMID:Kinase switching in mesenchymal-like non-small cell lung cancer lines contributes to EGFR inhibitor resistance through pathway redundancy. 1869 32

The BCR-ABL kinase inhibitor imatinib mesylate is currently the standard therapy for patients with chronic myeloid leukemia (CML). However, mutations within the ABL kinase domain interfering with drug binding have been identified as the main mechanism of resistance to imatinib. Multiple distinct BCR-ABL kinase mutant isoforms conferring varying degrees of resistance to tyrosine kinase inhibitors have been reported. Nilotinib is a tyrosine kinase inhibitor 30-fold more potent than imatinib against BCR-ABL kinase. Nilotinib is active against a wide range of imatinib-resistant BCR-ABL mutant isoforms, except for T315I. Results from Phase II studies of nilotinib for patients with CML after failure or intolerance to imatinib therapy have shown a favorable toxicity profile and confirmed the high efficacy of nilotinib in this setting. Studies addressing the activity of nilotinib in newly-diagnosed patients with CML are underway. Furthermore, nilotinib is a potent inhibitor of KIT and PDGFR kinases. Here, we review the preclinical development of nilotinib and the activity of this agent in patients with CML and in tumors driven by KIT and/or PDGFR mutant kinases, such as gastrointestinal stromal tumors and some forms of clonal hypereosinophilia.
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PMID:Nilotinib: a phenylamino-pyrimidine derivative with activity against BCR-ABL, KIT and PDGFR kinases. 1892 18


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