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)

At the time of writing, there are seven marketed kinase inhibitor drugs. The first kinase inhibitor, imatinib mesilate (Gleevec, Novartis), came to market in 2001, an inhibitor of the breakpoint cluster region (BCR)/Abelson murine leukemia oncogene homolog (ABL) fusion, platelet-derived growth factor (PDGF) receptor, and c-kit kinases. The most recent kinase inhibitor to come to market, disatinib (Sprycel, Bristol-Myers Squibb), acts on c-SRC, ABL and Bruton's tyrosine kinase. To date, kinase inhibitor drugs are approved for oncology and demonstrate that it is possible to develop compounds with relative selectivity for the target kinase against the broader kinome. However, the use of kinase inhibitors in chronic inflammatory and immunologic diseases may require greater selectivity for the target kinase. This review addresses the opportunities and challenges of kinase inhibition as a therapeutic approach in chronic immune and inflammatory disease.
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PMID:Kinase inhibitors as drugs for chronic inflammatory and immunological diseases: progress and challenges. 1855 56

Imatinib is a selective tyrosine kinase inhibitor which acts on breakpoint cluster region-Abelson fusion gene (BCR-ABL) positive leukemia including all phases of chronic myeloid leukemia and acute lymphoblastic leukemia. It may induce rapid apoptosis and subsequent tumor lysis syndrome. Only 3 cases of imatinib-induced tumor lysis syndrome have been reported. We herein described an additional patient with BCR-ABL (ela2) positive acute lymphoblastic leukemia who developed tumor lysis syndrome after 10-day treatment with imatinib. Experience in the current case suggests that preventive measures for tumor lysis syndrome, including allopurinol and hydration, should be taken for patients with high leukemia burden who receive imatinib therapy, and parameters of tumor lysis should be monitored in the early phase of therapy.
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PMID:Imatinib-induced tumor lysis syndrome: report of a case and review of the literature. 1909 99

Resistance to imatinib in patients with chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) has emerged as a significant clinical issue. Dasatinib is a tyrosine kinase inhibitor that has 325-fold greater in vitro activity against native BCR-ABL (breakpoint cluster region-Abelson leukemia virus) compared with imatinib and can overcome primary (intrinsic) and secondary (acquired) imatinib resistance. Here, we review the clinical profile of dasatinib in imatinib-resistant and -intolerant patients and share clinical approaches for managing adverse events (AEs) to ensure maximum patient benefit. References were obtained through literature searches on PubMed as well as from the Proceedings of Annual Meetings of the American Society of Clinical Oncology, the American Society of Hematology, and European Hematology Association. Phase II and III studies of dasatinib in patients with imatinib-resistant or -intolerant CML in any phase or Ph+ ALL were selected for discussion. Dasatinib is currently indicated for the treatment of patients with imatinib-resistant or -intolerant CML or Ph+ ALL. AEs associated with dasatinib are typically mild to moderate, and are usually resolved with temporary treatment interruption and/or dose adjustments. A Phase III dose optimization study showed that in patients with chronic phase (CP) CML, 100 mg once-daily dasatinib improves the safety profile, particularly pleural effusion and thrombocytopenia, while maintaining efficacy compared with the previously recommended dose of 70 mg twice-daily. Dasatinib has a manageable safety profile. For patients with CP CML, a new recommended starting dose of 100 mg once daily has recently been approved. The recommended dose for patients with advanced CML or Ph+ ALL remains 70 mg twice daily.
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PMID:New dosing schedules of dasatinib for CML and adverse event management. 1923 16

The JAK(V617F) mutation is responsible for the majority of breakpoint cluster region (BCR)/Abelson (ABL)-negative myeloproliferative disorders. Ongoing clinical trials of Janus kinase 2 (JAK2) inhibitors in myeloproliferative disorder patients use small molecules targeting both wild-type and mutated JAK2. To selectively target malignant cells, we developed JAK2(V617F)-specific small interfering RNAs or short hairpin RNAs. Expression of these RNAs in cell lines or CD34(+) cells from patients reduced JAK2(V617F)-driven autonomous cell proliferation. Mechanisms of inhibition involved selective JAK2(V617F) protein down-regulation, and consequently, decrease in signal transducer and activator of transcription 5 phosphorylation, cell-cycle progression, and cell survival. However, the addition of high concentrations of cytokines to cell lines or erythropoietin to patient cells greatly reduced growth inhibition. Similarly, the efficacy of a JAK2 small molecule inhibitor on cell line and patient cell proliferation dose dependently decreased with the addition of cytokines. Our results demonstrate that it is possible to specifically target JAK2(V617F) by RNA interference (RNAi) strategies. In addition, cytokines partially reverse the inhibition induced by both RNAi and small molecule approaches. This strongly suggests that patient cytokine levels in current JAK2 inhibitor clinical trials modulate the outcome of these therapies.
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PMID:Selective reduction of JAK2V617F-dependent cell growth by siRNA/shRNA and its reversal by cytokines. 1958 25

The discovery of the Philadelphia (Ph) chromosome represented the first step towards understanding the molecular basis of haematological malignancies. Subsequent developments including the characterisation of t(9;22)(q34;q11) translocation, the identification of the breakpoint cluster region as well as the demonstration that retrovirally mediated insertion of a human BCR-ABL gene into murine haematopoietic stem cells induced a leukaemia-like picture and the creation of BCR-ABL transgenic mice established the central role of BCR-ABL in chronic myeloid leukaemia (CML) beyond all reasonable doubt. Many years later an important goal was achieved, that is, the use of BCR-ABL as a therapeutic target. However, it is uncertain whether the BCR-ABL fusion gene is really the initiating lesion for the chronic phase of CML. There is an incomplete understanding of the so-called genomic instability that underlies the production of the fusion gene and predisposes the Ph-positive clone to acquire further genetic events leading to advanced-phase disease.
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PMID:CML: a model for targeted therapy. 1995 80

The real-time quantitative reverse transcriptase polymerase chain reaction (RQ-PCR) has become the method of choice for the quantification of specific mRNAs. This method is fast, extremely sensitive, and accurate, requires only very small amounts of input RNA, and is relatively simple to perform. These characteristics have made it the method of choice for minimal residual disease monitoring such as in chronic myelogenous leukemia (CML). CML comprises approximately 20% of all leukemias and is characterized by a balanced (9;22) chromosomal translocation that results in the formation of a chimeric gene comprised of the BCR (breakpoint cluster region) gene and the ABL oncogene (BCR-ABL fusion gene). The chimeric gene encodes a fusion protein with constitutively increased tyrosine kinase activity, resulting in growth factor-independent proliferation. This kinase is the target for current CML therapy, and BCR-ABL fusion gene levels are monitored to determine the effectiveness of this therapy. This chapter uses BCR-ABL transcript detection to illustrate an example for the RQ-PCR and describes a RQ-PCR method to detect the most common form of the BCR-ABL fusion transcript in CML, known as p210 BCR-ABL.
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PMID:Real-time quantitative reverse transcriptase polymerase chain reaction. 2030 Sep 99

We identified a novel breakpoint cluster region-ABL rearrangement in a chronic myeloid leukemia (CML) patient. The e14/a2 (b3/a2) type BCR-ABL mRNA incorporated a 42-nucleotide intronic insertion of ABL intron Ib between BCR exon e14 and ABL exon a2. As we hypothesized that the rearrangement between BCR and ABL genes occurred near the inserted sequence and because of the relative small size of BCR intron 14, we determined the BCR-ABL breakpoint at the genomic DNA level. Using a PCR-based method, this analysis revealed that i) BCR intron 14 brought a potential lariat branch point and the polypyrimidine tract, ii) the BCR-ABL breakpoint created a chimeric acceptor site, and iii) the inserted sequence of ABL intron Ib carried at its 3' end a well-conserved donor splice site. Therefore, the inserted sequence was flanked by canonical consensus splice sites and recognized as a pseudo-exon (as shown by splice site prediction and exon finder software). Moreover, the insertion did not disrupt the reading frame between BCR and ABL and did not produce a premature stop codon. Instead, this novel BCR-ABL chimeric transcript encoded a functional oncoprotein with an in-frame insertion of 15 new amino acids.
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PMID:Comprehensive characterization of a novel intronic pseudo-exon inserted within an e14/a2 BCR-ABL rearrangement in a patient with chronic myeloid leukemia. 2050 29

The BCR-ABL1 fusion gene results from a reciprocal translocation rearrangement, t(9;22)(q34;q11.2), and is a hallmark of chronic myeloid leukemia (CML). The breakpoint on chromosome 9 is mostly 5' to ABL1 exon 2, whereas on chromosome 22, the breakpoint can occur in various regions involving the major breakpoint cluster region (M-bcr) in CML and the minor breakpoint cluster region (m-bcr) in acute lymphoblastic leukemia. Described here is a rare case of Philadelphia-positive CML with intronic splice sites. This atypical BCR-ABL1 transcript was detected along with a classic e13a2 transcript, using reverse transcription polymerase chain reaction (RT-PCR). Nucleotide sequence analysis revealed a joining of BCR intron 13 with ABL1 intron 1a. Both transcripts were detected when the patient was on hydroxyurea treatment; with imatinib mesylate therapy, the atypical transcript disappeared. To our knowledge, this is the first report of BCR-ABL1 transcript with breakpoint occurring within both BCR and ABL1 introns and fusion of intronic sequences from both BCR and ABL1 genes.
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PMID:A unique BCR-ABL1 transcript with the insertion of intronic sequence from BCR and ABL1 genes in a patient with Philadelphia-positive chronic myeloid leukemia: a case study. 2063 71

Advances in the generation and interpretation of proteomics data have spurred a transition from focusing on protein identification to functional analysis. Here we review recent proteomics results that have elucidated new aspects of the roles and regulation of signal transduction pathways in cancer using the epidermal growth factor receptor (EGFR), ERK and breakpoint cluster region (BCR)-ABL1 networks as examples. The emerging theme is to understand cancer signalling as networks of multiprotein machines which process information in a highly dynamic environment that is shaped by changing protein interactions and post-translational modifications (PTMs). Cancerous genetic mutations derange these protein networks in complex ways that are tractable by proteomics.
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PMID:Functional proteomics to dissect tyrosine kinase signalling pathways in cancer. 2072 May 70

Around 40-50% of patients with chronic myeloid leukemia (CML) who achieve a stable complete molecular response (CMR; undetectable breakpoint cluster region-Abelson leukemia gene human homolog 1 (BCR-ABL1) mRNA) on imatinib can stop therapy and remain in CMR, at least for several years. This raises the possibility that imatinib therapy may not need to be continued indefinitely in some CML patients. Two possible explanations for this observation are (1) CML has been eradicated or (2) residual leukemic cells fail to proliferate despite the absence of ongoing kinase inhibition. We used a highly sensitive patient-specific nested quantitative PCR to look for evidence of genomic BCR-ABL1 DNA in patients who sustained CMR after stopping imatinib therapy. Seven of eight patients who sustained CMR off therapy had BCR-ABL1 DNA detected at least once after stopping imatinib, but none has relapsed (follow-up 12-41 months). BCR-ABL1 DNA levels increased in all of the 10 patients who lost CMR soon after imatinib cessation, whereas serial testing of patients in sustained CMR showed a stable level of BCR-ABL1 DNA. This more sensitive assay for BCR-ABL1 provides evidence that even patients who maintain a CMR after stopping imatinib may harbor residual leukemia. A search for intrinsic or extrinsic (for example, immunological) causes for this drug-free leukemic suppression is now indicated.
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PMID:Patients with chronic myeloid leukemia who maintain a complete molecular response after stopping imatinib treatment have evidence of persistent leukemia by DNA PCR. 2081 3


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