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)

Dasatinib is a small-molecule inhibitor of multiple tyrosine kinases, including BCR-ABL, SRC, c-KIT, ephrin A receptor and platelet-derived growth factor-beta receptor kinases, at nanomolar concentrations. In vitro, dasatinib is 325-fold more potent than imatinib against cells expressing wild-type BCR-ABL. The efficacy and tolerability of oral dasatinib has been established in the START phase II trials in adults with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) who were intolerant or resistant to imatinib, and optimal dasatinib dosage regimens were identified in phase III randomized trials. In patients with chronic phase CML, the major cytogenetic response rate in the START-C trial (median follow-up 15.2 months) was 59% with dasatinib, and in the randomized START-R trial (median follow-up 15 months), was greater with dasatinib than with high-dose imatinib (52% vs 33%). Major hematologic response rates with dasatinib were 63% in patients with accelerated phase CML (follow-up > or =9 months; START-A trial), 34% in patients with myeloid blast phase CML and 35% in those with lymphoid blast phase CML (follow-up > or =12 months; START-B and START-L trials), and 41% in patients with Ph-positive ALL (follow-up > or =12 months; START-L trial). Based on phase III results, a once-daily dasatinib regimen is considered optimal in chronic phase CML (starting dosage 100 mg once daily), while a twice-daily regimen continues to be recommended in accelerated phase, myeloid blast phase or lymphoid blast phase CML and Ph-positive ALL (starting dosage 70 mg twice daily). Adverse events were frequent in patients treated with dasatinib, but most were mild to moderate in severity. Grade 3/4 adverse events were uncommon and were clinically manageable.
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PMID:Dasatinib: in chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. 1821 92

Transient pancytopenia preceding acute lymphoblastic leukemia (pre-ALL) is a rare but well-known occurrence usually affecting children and adolescents. Though pre-ALL in a few adults has ever been reported, the association of this preleukemic syndrome with positive Philadelphia chromosome and P190(BCR-ABL) is extremely rare. To the best of our knowledge, this is the first report of adult B-cell type pre-ALL with positive Philadelphia chromosome and P190(BCR-ABL) published in the literature. We report the case of a 49-year-old woman who was diagnosed with B-cell type ALL associated positive Philadelphia chromosome and P190(BCR-ABL) preceded by transient pancytopenia. The clinical, morphologic, immunophenotypic and molecular features of this patient are described and the literature reviewed.
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PMID:Transient pancytopenia preceding acute lymphoblastic leukemia with positive Philadelphia chromosome. 1829 24

Amplification of the NUP214-ABL1 oncogene can be detected in patients with T cell acute lymphoblastic leukemia (T-ALL). We screened 29 patients with T cell malignancies for the expression of NUP214-ABL1 by reverse transcription-polymerase chain reaction (RT-PCR). NUP214-ABL1 was detected in three (10%) patients. These results were confirmed by fluorescence in situ hybridization techniques. We also studied the activity of imatinib, nilotinib and dasatinib against the human NUP214-ABL1-positive cell lines PEER and BE-13. All three tyrosine kinase inhibitors decreased the viability of PEER and BE-13 cells, but nilotinib and dasatinib had >1-log lower IC(50) values than imatinib (P<0.001). In contrast, the NUP214-ABL-negative T-ALL cell line Jurkat, was remarkably resistant to tyrosine kinase inhibition. The inhibition of cellular proliferation was associated with time-dependent induction of apoptosis and inhibition of ABL, CrKL and STAT5 phosphorylation. Moreover, dasatinib was active in a NUP214-ABL1-positive leukemia xenograft murine model and in marrow lymphoblasts from a patient with NUP214-ABL1-positive T-ALL. On the basis of these results, ABL1 kinase inhibitors warrant clinical investigation in patients with NUP214-ABL1-positive T-cell malignancies.
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PMID:Activity of tyrosine kinase inhibitors against human NUP214-ABL1-positive T cell malignancies. 1840 17

Imatinib is a small-molecule inhibitor of BCR-ABL tyrosine kinase activity, with proven efficacy and tolerability. Despite imatinib's activity, the development of resistance, whether BCR-ABL dependent or independent, is a concern. BCR-ABL-dependent resistance is commonly a result of mutations in the BCR-ABL gene, which can induce a structural predisposition towards the active conformation of the protein, resulting in a shift in the equilibrium of BCR-ABL from inactive, which imatinib binds, to active, which imatinib is unable to bind. BCR-ABL gene amplification may play a role in the development of imatinib resistance in patients with CML. There are a number of BCR-ABL-independent mechanisms of imatinib resistance, including the efflux protein multidrug resistance protein-1, of which imatinib is a substrate. Another mechanism may be the development of alternative pathways of disease progression, leading to less reliance on BCR-ABL; indeed, the SRC family tyrosine kinases LYN and HCK have been frequently implicated in treatment resistance and progression of CML. Clearly, imatinib resistance requires the development of other treatment options. Dasatinib, with increased binding potency (325-fold greater potency than imatinib for wild-type BCR-ABL), inhibition of both the active and inactive formation of BCR-ABL, and targeting of SRC family kinases, is the only agent approved for the treatment of patients with imatinib-resistant or -intolerant CML and Ph+ ALL. Dasatinib is highly active in all phases of these diseases, and is active in the majority of imatinib-resistant mutations, with the exception of T315I. The development of agents that effectively inhibit T315I mutations suggests that future treatment options will include combination therapy.
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PMID:Overcoming kinase resistance in chronic myeloid leukemia. 1840 81

Ikaros is a zinc-finger transcriptional factor playing an essential role in lymphoid lineage commitment and differentiation. Animal models and analysis of human Ikaros in leukemic cells demonstrate deregulation of Ikaros expression. Short isoforms with a truncated DNA-binding domain suppress functions of Ikaros in a dominant-negative manner. Previous studies demonstrated that human leukemias are heterogeneous for Ikaros expression. We estimate the relative level of Ikaros mRNA transcripts in 80 childhood ALL cases in comparison with AML and healthy donor groups. We detected eight major isoforms and several minor mutant isoforms in most patients with acute lymphoblastic and myeloid leukemia and in healthy donors, but the relative level of expression varied. The relatively high level of Ik4A isoform, rarely mentioned in previous reports, was detected in all analyzed groups. The ratio between functional and all isoforms was used to determine functional activity of Ikaros. The ratio was significantly less in AML (p=0.027) and BCR-ABL positive ALL (p=0.0028) than in healthy bone marrow. We found a negative association between the Ikaros ratio and myeloid coexpression in B-cell ALL, the most prominent was for CD15. The Ikaros ratio positively correlates with CD5 and negatively with CD7 expression in T-ALL. We suggest that an anti-proliferation and anti-activation effect of full-length Ikaros may be mediated through regulation of CD5 and CD7.
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PMID:Relative expression of different Ikaros isoforms in childhood acute leukemia. 1867 65

Some cases of pre-B cell acute lymphoblastic leukemia (pre-B-ALL) are caused by the Philadelphia (Ph) chromosome-encoded BCR-ABL oncogene, and these tend to have a poor prognosis. Inhibitors of the PI3K/AKT pathway reduce BCR-ABL-mediated transformation in vitro; however, the specific PI3K isoforms involved are poorly defined. Using a murine model of Ph+ pre-B-ALL, we found that deletion of both Pik3r1 and Pik3r2, genes encoding class IA PI3K regulatory isoforms, severely impaired transformation. BCR-ABL-dependent pre/pro-B cell lines could be established at low frequency from progenitors that lacked these genes, but the cells were smaller, proliferated more slowly, and failed to cause leukemia in vivo. These cell lines displayed nearly undetectable PI3K signaling function and were resistant to the PI3K inhibitor wortmannin. However, they maintained activation of mammalian target of rapamycin (mTOR) and were more sensitive to rapamycin. Treatment with rapamycin caused feedback activation of AKT in WT cell lines but not PI3K-deficient lines. A dual inhibitor of PI3K and mTOR, PI-103, was more effective than rapamycin at suppressing proliferation of mouse pre-B-ALL and human CD19+CD34+)Ph+ ALL leukemia cells treated with the ABL kinase inhibitor imatinib. Our findings provide mechanistic insights into PI3K dependency in oncogenic networks and provide a rationale for targeting class IA PI3K, alone or together with mTOR, in the treatment of Ph+ ALL.
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PMID:Ablation of PI3K blocks BCR-ABL leukemogenesis in mice, and a dual PI3K/mTOR inhibitor prevents expansion of human BCR-ABL+ leukemia cells. 2856 34

The BCR/ABL tyrosine kinase inhibitor, imatinib mesylate, has shown substantial effects in chronic myelogenous leukemia (CML) and Ph-positive acute lymphoblastic leukemia (Ph(+)ALL). However, most patients relapse after an initial clinical response, indicating that drug resistance is a major problem in patients on imatinib. It is a serious problem that effective treatment choices to T315I, in the ABL kinase domain that shows a strong tolerance in imatinib do not exist clinically. In this study, we propose a new therapeutic approach to Ph(+)ALL with the T315I. Here, we report that the serine/threonine kinase mTOR (the mammalian target of rapamycin) inhibitor, rapamycin, inhibits the growth of not only the Bcr-Abl-positive lymphoid leukemic cell line, SU-Ph2, established from Ph(+)ALL patients, but also the imatinib-resistant cell line, SU/SR, that has acquired T315I. Rapamycin significantly inhibits cell growth in both these cell lines, and easily induces apoptosis at the same dose, thereby acting as an immunosuppressive agent. Our result suggested that the mTOR-signaling pathway has become an important therapeutic target for Ph-positive leukemias in the future, and at the same time, it is also becoming a very effective tool for the treatment of Ph(+)ALL with T315I.
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PMID:Hypersensitivity of Ph-positive lymphoid cell lines to rapamycin: Possible clinical application of mTOR inhibitor. 1878 28

Episomes with the NUP214-ABL1 fusion gene have been observed in 6% of T-ALL. In this multicentric study we collected 27 cases of NUP214-ABL1-positive T-ALL. Median age was 15 years with male predominance. Outcome was poor in 12 patients. An associated abnormality involving TLX1 or TLX3 was found in all investigated cases. Fluorescent in situ hybridization revealed a heterogeneous pattern of NUP214-ABL1 amplification. Multiple episomes carrying the fusion were detected in 24 patients. Episomes were observed in a significant number of nuclei in 18 cases, but in only 1-5% of nuclei in 6. In addition, intrachromosomal amplification (small hsr) was identified either as the only change or in association with episomes in four cases and two T-ALL cell lines (PEER and ALL-SIL). One case showed insertion of apparently non-amplified NUP214-ABL1 sequences at 14q12. The amplified sequences were analyzed using array-based CGH.These findings confirm that the NUP214-ABL1 gene requires amplification for oncogenicity; it is part of a multistep process of leukemogenesis; and it can be a late event present only in subpopulations. Data also provide in vivo evidence for a model of episome formation, amplification and optional reintegration into the genome. Implications for the use of kinase inhibitors are discussed.
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PMID:Heterogeneous patterns of amplification of the NUP214-ABL1 fusion gene in T-cell acute lymphoblastic leukemia. 1892 37

Senescence and apoptosis programs governed by the Rb and p53 signaling networks can counter tissue stem cell self-renewal. A master regulator of Rb and p53 is the INK4-ARF (CDKN2A/B) locus that encodes two CDK inhibitors, p16(INK4A) and p15(INK4B), that maintain Rb in its active, hypophosphorylated form, and p14(ARF) (p19(Arf) in mice), that inhibits Mdm2 and activates p53. The INK4-ARF genes are epigenetically silenced in hematopoietic stem cells but become poised to respond to oncogenic stress as blood cells differentiate. Inactivation of INK4-ARF endows differentiated cells with an inappropriate self-renewal capacity, a defining feature of cancer cells. In BCR-ABL-induced (Philadelphia chromosome-positive [Ph(+)]) leukemias, INK4-ARF deletions frequently occur in clinically aggressive acute lymphoblastic leukemias (Ph(+) ALLs) but are not seen in more indolent Ph(+) chronic myelogenous leukemia (CML) or in CML myeloid blast crisis. Mouse modeling of Ph(+) ALL reveals that Arf inactivation attenuates responsiveness to targeted BCR-ABL kinase inhibitors, enhances the maintenance of leukemia-initiating cells within the hematopoietic microenvironment, and facilitates the emergence of malignant clones that harbor drug-resistant BCR-ABL kinase mutations. Thus, although BCR-ABL mutations typify drug resistance in both CML and Ph(+) ALL, loss of INK4-ARF in Ph(+) ALL enhances disease aggressiveness and undermines the salutary effects of targeted therapy.
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PMID:The INK4-ARF (CDKN2A/B) locus in hematopoiesis and BCR-ABL-induced leukemias. 1902 87

The advent of imatinib, a selective inhibitor of the ABL tyrosine kinase, has revolutionized the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Combined with chemotherapy, imatinib exerts remarkable efficacy in patients with newly diagnosed disease with a complete remission (CR) rate of 95% and a survival rate of 55% at 3 years. Profound eradication of leukemia cells not only provides patients with a better chance for receiving allogeneic hematopoietic stem cell transplantation during first CR but also contributes to durable CR even without transplantation. Despite such improvement, however, relapse does occur, mainly owing to acquisition of resistance. Growing comprehension of the molecular mechanisms of resistance to imatinib has led to the development of novel BCR-ABL inhibitors that yield higher affinity for BCR-ABL and/or potent inhibitory activity against other target molecules such as SRC family kinases. The second-generation ABL kinase inhibitors, namely dasatinib and nilotinib, are already showing clinical activity in patients with imatinib-resistant Ph+ ALL, and other novel agents are undergoing preclinical and early clinical evaluation. Further improvement in treatment results will be achieved by identifying each patient's disease profile based on information obtained before and during treatment and by optimizing subsequent treatment accordingly.
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PMID:Recent advances in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. 1909 66


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