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  • 1
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    Activating mutations in ALK provide a therapeutic target in neuroblastoma (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-10-17
    Description: Neuroblastoma, an embryonal tumour of the peripheral sympathetic nervous system, accounts for approximately 15% of all deaths due to childhood cancer. High-risk neuroblastomas are rapidly progressive; even with intensive myeloablative chemotherapy, relapse is common and almost uniformly fatal. Here we report the detection of previously unknown mutations in the ALK gene, which encodes a receptor tyrosine kinase, in 8% of primary neuroblastomas. Five non-synonymous sequence variations were identified in the kinase domain of ALK, of which three were somatic and two were germ line. The most frequent mutation, F1174L, was also identified in three different neuroblastoma cell lines. ALK complementary DNAs encoding the F1174L and R1275Q variants, but not the wild-type ALK cDNA, transformed interleukin-3-dependent murine haematopoietic Ba/F3 cells to cytokine-independent growth. Ba/F3 cells expressing these mutations were sensitive to the small-molecule inhibitor of ALK, TAE684 (ref. 4). Furthermore, two human neuroblastoma cell lines harbouring the F1174L mutation were also sensitive to the inhibitor. Cytotoxicity was associated with increased amounts of apoptosis as measured by TdT-mediated dUTP nick end labelling (TUNEL). Short hairpin RNA (shRNA)-mediated knockdown of ALK expression in neuroblastoma cell lines with the F1174L mutation also resulted in apoptosis and impaired cell proliferation. Thus, activating alleles of the ALK receptor tyrosine kinase are present in primary neuroblastoma tumours and in established neuroblastoma cell lines, and confer sensitivity to ALK inhibition with small molecules, providing a molecular rationale for targeted therapy of this disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2587486/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2587486/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉George, Rani E -- Sanda, Takaomi -- Hanna, Megan -- Frohling, Stefan -- Luther, William 2nd -- Zhang, Jianming -- Ahn, Yebin -- Zhou, Wenjun -- London, Wendy B -- McGrady, Patrick -- Xue, Liquan -- Zozulya, Sergey -- Gregor, Vlad E -- Webb, Thomas R -- Gray, Nathanael S -- Gilliland, D Gary -- Diller, Lisa -- Greulich, Heidi -- Morris, Stephan W -- Meyerson, Matthew -- Look, A Thomas -- CA21765/CA/NCI NIH HHS/ -- CA69129/CA/NCI NIH HHS/ -- K08 NS047983/NS/NINDS NIH HHS/ -- K08 NS047983-03/NS/NINDS NIH HHS/ -- K08 NS047983-04/NS/NINDS NIH HHS/ -- K08 NS047983-05/NS/NINDS NIH HHS/ -- England -- Nature. 2008 Oct 16;455(7215):975-8. doi: 10.1038/nature07397.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pediatric Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18923525" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Apoptosis ; Cell Line, Tumor ; Cell Proliferation ; Cell Survival ; Enzyme Activation/genetics ; Genome, Human/genetics ; Humans ; In Situ Hybridization, Fluorescence ; In Situ Nick-End Labeling ; Mice ; Mutation/*genetics ; Neuroblastoma/enzymology/*genetics/pathology/*therapy ; Polymorphism, Single Nucleotide/genetics ; Protein Structure, Tertiary/genetics ; Protein-Tyrosine Kinases/*antagonists & inhibitors/chemistry/*genetics/metabolism ; Receptor Protein-Tyrosine Kinases ; Sequence Analysis, DNA
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
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    Novel mutant-selective EGFR kinase inhibitors against EGFR T790M (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-12-25
    Description: The clinical efficacy of epidermal growth factor receptor (EGFR) kinase inhibitors in EGFR-mutant non-small-cell lung cancer (NSCLC) is limited by the development of drug-resistance mutations, including the gatekeeper T790M mutation. Strategies targeting EGFR T790M with irreversible inhibitors have had limited success and are associated with toxicity due to concurrent inhibition of wild-type EGFR. All current EGFR inhibitors possess a structurally related quinazoline-based core scaffold and were identified as ATP-competitive inhibitors of wild-type EGFR. Here we identify a covalent pyrimidine EGFR inhibitor by screening an irreversible kinase inhibitor library specifically against EGFR T790M. These agents are 30- to 100-fold more potent against EGFR T790M, and up to 100-fold less potent against wild-type EGFR, than quinazoline-based EGFR inhibitors in vitro. They are also effective in murine models of lung cancer driven by EGFR T790M. Co-crystallization studies reveal a structural basis for the increased potency and mutant selectivity of these agents. These mutant-selective irreversible EGFR kinase inhibitors may be clinically more effective and better tolerated than quinazoline-based inhibitors. Our findings demonstrate that functional pharmacological screens against clinically important mutant kinases represent a powerful strategy to identify new classes of mutant-selective kinase inhibitors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879581/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879581/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhou, Wenjun -- Ercan, Dalia -- Chen, Liang -- Yun, Cai-Hong -- Li, Danan -- Capelletti, Marzia -- Cortot, Alexis B -- Chirieac, Lucian -- Iacob, Roxana E -- Padera, Robert -- Engen, John R -- Wong, Kwok-Kin -- Eck, Michael J -- Gray, Nathanael S -- Janne, Pasi A -- P50CA090578/CA/NCI NIH HHS/ -- R01 CA122794/CA/NCI NIH HHS/ -- R01 CA130876/CA/NCI NIH HHS/ -- R01 CA130876-02/CA/NCI NIH HHS/ -- R01 CA135257/CA/NCI NIH HHS/ -- R01AG2400401/AG/NIA NIH HHS/ -- R01CA080942/CA/NCI NIH HHS/ -- R01CA11446/CA/NCI NIH HHS/ -- R01CA116020/CA/NCI NIH HHS/ -- R01CA130876-02/CA/NCI NIH HHS/ -- R01CA135257/CA/NCI NIH HHS/ -- R01GM070590/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Dec 24;462(7276):1070-4. doi: 10.1038/nature08622.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cancer Biology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20033049" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antineoplastic Agents/chemistry/*pharmacology/toxicity ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Drug Evaluation, Preclinical ; Drug Resistance, Neoplasm/genetics ; Lung/drug effects ; Mice ; Models, Chemical ; Models, Molecular ; Mutation/*genetics ; NIH 3T3 Cells ; Phosphorylation/drug effects ; Protein Kinase Inhibitors/chemistry/*pharmacology/toxicity ; Receptor, Epidermal Growth Factor/*antagonists & inhibitors/*genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
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    Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-01-15
    Description: In an effort to find new pharmacological modalities to overcome resistance to ATP-binding-site inhibitors of Bcr-Abl, we recently reported the discovery of GNF-2, a selective allosteric Bcr-Abl inhibitor. Here, using solution NMR, X-ray crystallography, mutagenesis and hydrogen exchange mass spectrometry, we show that GNF-2 binds to the myristate-binding site of Abl, leading to changes in the structural dynamics of the ATP-binding site. GNF-5, an analogue of GNF-2 with improved pharmacokinetic properties, when used in combination with the ATP-competitive inhibitors imatinib or nilotinib, suppressed the emergence of resistance mutations in vitro, displayed additive inhibitory activity in biochemical and cellular assays against T315I mutant human Bcr-Abl and displayed in vivo efficacy against this recalcitrant mutant in a murine bone-marrow transplantation model. These results show that therapeutically relevant inhibition of Bcr-Abl activity can be achieved with inhibitors that bind to the myristate-binding site and that combining allosteric and ATP-competitive inhibitors can overcome resistance to either agent alone.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2901986/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2901986/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Jianming -- Adrian, Francisco J -- Jahnke, Wolfgang -- Cowan-Jacob, Sandra W -- Li, Allen G -- Iacob, Roxana E -- Sim, Taebo -- Powers, John -- Dierks, Christine -- Sun, Fangxian -- Guo, Gui-Rong -- Ding, Qiang -- Okram, Barun -- Choi, Yongmun -- Wojciechowski, Amy -- Deng, Xianming -- Liu, Guoxun -- Fendrich, Gabriele -- Strauss, Andre -- Vajpai, Navratna -- Grzesiek, Stephan -- Tuntland, Tove -- Liu, Yi -- Bursulaya, Badry -- Azam, Mohammad -- Manley, Paul W -- Engen, John R -- Daley, George Q -- Warmuth, Markus -- Gray, Nathanael S -- R01 CA130876/CA/NCI NIH HHS/ -- R01 CA130876-03/CA/NCI NIH HHS/ -- England -- Nature. 2010 Jan 28;463(7280):501-6. doi: 10.1038/nature08675. Epub 2010 Jan 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Dana-Farber Cancer Institute, Harvard Medical School, Department of Cancer Biology, Seeley G. Mudd Building 628, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20072125" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antineoplastic Agents/*chemistry/metabolism/*pharmacology ; Antineoplastic Combined Chemotherapy Protocols ; Benzamides ; Binding Sites ; Bone Marrow Transplantation ; Cell Line, Tumor ; Crystallization ; Disease Models, Animal ; Drug Resistance, Neoplasm/*drug effects ; Female ; Fusion Proteins, bcr-abl/*chemistry/genetics/metabolism ; Humans ; Imatinib Mesylate ; Inhibitory Concentration 50 ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug ; therapy/enzymology/*metabolism ; Male ; Mass Spectrometry ; Mice ; Models, Molecular ; Mutation/genetics ; Piperazines/chemistry/pharmacology ; Protein Structure, Tertiary ; Pyrimidines/chemistry/metabolism/pharmacology ; Transplantation, Heterologous
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
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    A unifying model for mTORC1-mediated regulation of mRNA translation (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-05-04
    Description: The mTOR complex 1 (mTORC1) kinase nucleates a pathway that promotes cell growth and proliferation and is the target of rapamycin, a drug with many clinical uses. mTORC1 regulates messenger RNA translation, but the overall translational program is poorly defined and no unifying model exists to explain how mTORC1 differentially controls the translation of specific mRNAs. Here we use high-resolution transcriptome-scale ribosome profiling to monitor translation in mouse cells acutely treated with the mTOR inhibitor Torin 1, which, unlike rapamycin, fully inhibits mTORC1 (ref. 2). Our data reveal a surprisingly simple model of the mRNA features and mechanisms that confer mTORC1-dependent translation control. The subset of mRNAs that are specifically regulated by mTORC1 consists almost entirely of transcripts with established 5' terminal oligopyrimidine (TOP) motifs, or, like Hsp90ab1 and Ybx1, with previously unrecognized TOP or related TOP-like motifs that we identified. We find no evidence to support proposals that mTORC1 preferentially regulates mRNAs with increased 5' untranslated region length or complexity. mTORC1 phosphorylates a myriad of translational regulators, but how it controls TOP mRNA translation is unknown. Remarkably, loss of just the 4E-BP family of translational repressors, arguably the best characterized mTORC1 substrates, is sufficient to render TOP and TOP-like mRNA translation resistant to Torin 1. The 4E-BPs inhibit translation initiation by interfering with the interaction between the cap-binding protein eIF4E and eIF4G1. Loss of this interaction diminishes the capacity of eIF4E to bind TOP and TOP-like mRNAs much more than other mRNAs, explaining why mTOR inhibition selectively suppresses their translation. Our results clarify the translational program controlled by mTORC1 and identify 4E-BPs and eIF4G1 as its master effectors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3347774/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3347774/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Thoreen, Carson C -- Chantranupong, Lynne -- Keys, Heather R -- Wang, Tim -- Gray, Nathanael S -- Sabatini, David M -- CA103866/CA/NCI NIH HHS/ -- CA129105/CA/NCI NIH HHS/ -- R01 CA103866/CA/NCI NIH HHS/ -- R01 CA103866-08/CA/NCI NIH HHS/ -- R01 CA129105/CA/NCI NIH HHS/ -- R01 CA129105-05/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 May 2;485(7396):109-13. doi: 10.1038/nature11083.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cancer Biology, Dana Farber Cancer Institute, 250 Longwood Avenue, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22552098" target="_blank"〉PubMed〈/a〉
    Keywords: 5' Untranslated Regions/genetics ; Animals ; Base Sequence ; Cell Line, Tumor ; Eukaryotic Initiation Factor-4E/metabolism ; Eukaryotic Initiation Factor-4G/metabolism ; *Gene Expression Regulation/drug effects ; Humans ; Male ; Mice ; *Models, Biological ; Multiprotein Complexes ; Naphthyridines/pharmacology ; Nucleotide Motifs ; Phosphorylation ; Prostatic Neoplasms/genetics/pathology ; Protein Binding ; *Protein Biosynthesis/drug effects ; Proteins/antagonists & inhibitors/*metabolism ; RNA, Messenger/genetics/metabolism ; Ribosomes/metabolism ; TOR Serine-Threonine Kinases
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
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    Targeting transcription regulation in cancer with a covalent CDK7 inhibitor (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-07-22
    Description: Tumour oncogenes include transcription factors that co-opt the general transcriptional machinery to sustain the oncogenic state, but direct pharmacological inhibition of transcription factors has so far proven difficult. However, the transcriptional machinery contains various enzymatic cofactors that can be targeted for the development of new therapeutic candidates, including cyclin-dependent kinases (CDKs). Here we present the discovery and characterization of a covalent CDK7 inhibitor, THZ1, which has the unprecedented ability to target a remote cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7. Cancer cell-line profiling indicates that a subset of cancer cell lines, including human T-cell acute lymphoblastic leukaemia (T-ALL), have exceptional sensitivity to THZ1. Genome-wide analysis in Jurkat T-ALL cells shows that THZ1 disproportionally affects transcription of RUNX1 and suggests that sensitivity to THZ1 may be due to vulnerability conferred by the RUNX1 super-enhancer and the key role of RUNX1 in the core transcriptional regulatory circuitry of these tumour cells. Pharmacological modulation of CDK7 kinase activity may thus provide an approach to identify and treat tumour types that are dependent on transcription for maintenance of the oncogenic state.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4244910/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4244910/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kwiatkowski, Nicholas -- Zhang, Tinghu -- Rahl, Peter B -- Abraham, Brian J -- Reddy, Jessica -- Ficarro, Scott B -- Dastur, Anahita -- Amzallag, Arnaud -- Ramaswamy, Sridhar -- Tesar, Bethany -- Jenkins, Catherine E -- Hannett, Nancy M -- McMillin, Douglas -- Sanda, Takaomi -- Sim, Taebo -- Kim, Nam Doo -- Look, Thomas -- Mitsiades, Constantine S -- Weng, Andrew P -- Brown, Jennifer R -- Benes, Cyril H -- Marto, Jarrod A -- Young, Richard A -- Gray, Nathanael S -- CA109901/CA/NCI NIH HHS/ -- CA178860-01/CA/NCI NIH HHS/ -- HG002668/HG/NHGRI NIH HHS/ -- P01 NS047572/NS/NINDS NIH HHS/ -- P01 NS047572-10/NS/NINDS NIH HHS/ -- P30 CA014051/CA/NCI NIH HHS/ -- R01 CA130876/CA/NCI NIH HHS/ -- R01 CA130876-04/CA/NCI NIH HHS/ -- R01 CA179483/CA/NCI NIH HHS/ -- R01 HG002668/HG/NHGRI NIH HHS/ -- R21 CA178860/CA/NCI NIH HHS/ -- T32 GM008042/GM/NIGMS NIH HHS/ -- U54 HG006097/HG/NHGRI NIH HHS/ -- U54 HG006097-02/HG/NHGRI NIH HHS/ -- England -- Nature. 2014 Jul 31;511(7511):616-20. doi: 10.1038/nature13393. Epub 2014 Jun 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA [4]. ; 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA [3]. ; Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA. ; 1] Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. ; Department of Medicine Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts 02129, USA. ; 1] Department of Medicine Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts 02129, USA [2] Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA. ; 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada. ; 1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA [2] Cancer Science Institute of Singapore, National University of Singapore, 117599 Singapore. ; Chemical Kinomics Research Center, Korea Institute of Science and Technology, 39-1, Hawolgok-dong, Seongbuk-gu, Seoul 136-791, Korea, and KU-KIST Graduate School of Converging Science and Technology, 145, Anam-ro, Seongbuk-gu, Seoul 136-713, Korea. ; Daegu-Gyeongbuk Medical Innovation Foundation, 2387 dalgubeol-daero, Suseong-gu, Daegu 706-010, Korea. ; 1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA [2] Division of Hematology/Oncology, Children's Hospital, Boston, Massachusetts 02115 USA. ; 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043025" target="_blank"〉PubMed〈/a〉
    Keywords: Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Core Binding Factor Alpha 2 Subunit/metabolism ; Cyclin-Dependent Kinases/antagonists & inhibitors ; Cysteine/metabolism ; Enzyme Inhibitors/*pharmacology ; Gene Expression Regulation, Neoplastic/*drug effects ; Humans ; Jurkat Cells ; Phenylenediamines/*pharmacology ; Phosphorylation/drug effects ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/*enzymology ; Pyrimidines/*pharmacology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
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    Systematic identification of genomic markers of drug sensitivity in cancer cells (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-03-31
    Description: Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers for responses to targeted agents. Here, to uncover new biomarkers of sensitivity and resistance to cancer therapeutics, we screened a panel of several hundred cancer cell lines--which represent much of the tissue-type and genetic diversity of human cancers--with 130 drugs under clinical and preclinical investigation. In aggregate, we found that mutated cancer genes were associated with cellular response to most currently available cancer drugs. Classic oncogene addiction paradigms were modified by additional tissue-specific or expression biomarkers, and some frequently mutated genes were associated with sensitivity to a broad range of therapeutic agents. Unexpected relationships were revealed, including the marked sensitivity of Ewing's sarcoma cells harbouring the EWS (also known as EWSR1)-FLI1 gene translocation to poly(ADP-ribose) polymerase (PARP) inhibitors. By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3349233/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3349233/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Garnett, Mathew J -- Edelman, Elena J -- Heidorn, Sonja J -- Greenman, Chris D -- Dastur, Anahita -- Lau, King Wai -- Greninger, Patricia -- Thompson, I Richard -- Luo, Xi -- Soares, Jorge -- Liu, Qingsong -- Iorio, Francesco -- Surdez, Didier -- Chen, Li -- Milano, Randy J -- Bignell, Graham R -- Tam, Ah T -- Davies, Helen -- Stevenson, Jesse A -- Barthorpe, Syd -- Lutz, Stephen R -- Kogera, Fiona -- Lawrence, Karl -- McLaren-Douglas, Anne -- Mitropoulos, Xeni -- Mironenko, Tatiana -- Thi, Helen -- Richardson, Laura -- Zhou, Wenjun -- Jewitt, Frances -- Zhang, Tinghu -- O'Brien, Patrick -- Boisvert, Jessica L -- Price, Stacey -- Hur, Wooyoung -- Yang, Wanjuan -- Deng, Xianming -- Butler, Adam -- Choi, Hwan Geun -- Chang, Jae Won -- Baselga, Jose -- Stamenkovic, Ivan -- Engelman, Jeffrey A -- Sharma, Sreenath V -- Delattre, Olivier -- Saez-Rodriguez, Julio -- Gray, Nathanael S -- Settleman, Jeffrey -- Futreal, P Andrew -- Haber, Daniel A -- Stratton, Michael R -- Ramaswamy, Sridhar -- McDermott, Ultan -- Benes, Cyril H -- 086357/Wellcome Trust/United Kingdom -- 1U54HG006097-01/HG/NHGRI NIH HHS/ -- P41GM079575-02/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Mar 28;483(7391):570-5. doi: 10.1038/nature11005.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22460902" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line, Tumor ; Cell Survival/drug effects ; Drug Resistance, Neoplasm/drug effects/*genetics ; *Drug Screening Assays, Antitumor ; Gene Expression Regulation, Neoplastic/genetics ; Genes, Neoplasm/*genetics ; Genetic Markers/*genetics ; Genome, Human/*genetics ; Genomics ; Humans ; Indoles/pharmacology ; Neoplasms/*drug therapy/*genetics/pathology ; Oncogene Proteins, Fusion/genetics ; Pharmacogenetics ; Phthalazines/pharmacology ; Piperazines/pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors ; Proto-Oncogene Protein c-fli-1/genetics ; RNA-Binding Protein EWS/genetics ; Sarcoma, Ewing/drug therapy/genetics/pathology
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  • 7
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    The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling (2011)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2011-06-11
    Description: The mammalian target of rapamycin (mTOR) protein kinase is a master growth promoter that nucleates two complexes, mTORC1 and mTORC2. Despite the diverse processes controlled by mTOR, few substrates are known. We defined the mTOR-regulated phosphoproteome by quantitative mass spectrometry and characterized the primary sequence motif specificity of mTOR using positional scanning peptide libraries. We found that the phosphorylation response to insulin is largely mTOR dependent and that mTOR exhibits a unique preference for proline, hydrophobic, and aromatic residues at the +1 position. The adaptor protein Grb10 was identified as an mTORC1 substrate that mediates the inhibition of phosphoinositide 3-kinase typical of cells lacking tuberous sclerosis complex 2 (TSC2), a tumor suppressor and negative regulator of mTORC1. Our work clarifies how mTORC1 inhibits growth factor signaling and opens new areas of investigation in mTOR biology.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3177140/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3177140/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hsu, Peggy P -- Kang, Seong A -- Rameseder, Jonathan -- Zhang, Yi -- Ottina, Kathleen A -- Lim, Daniel -- Peterson, Timothy R -- Choi, Yongmun -- Gray, Nathanael S -- Yaffe, Michael B -- Marto, Jarrod A -- Sabatini, David M -- AI47389/AI/NIAID NIH HHS/ -- CA103866/CA/NCI NIH HHS/ -- CA112967/CA/NCI NIH HHS/ -- ES015339/ES/NIEHS NIH HHS/ -- GM68762/GM/NIGMS NIH HHS/ -- R01 CA103866/CA/NCI NIH HHS/ -- R01 CA103866-09/CA/NCI NIH HHS/ -- R01 CA129105/CA/NCI NIH HHS/ -- R01 CA129105-05/CA/NCI NIH HHS/ -- R37 AI047389/AI/NIAID NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2011 Jun 10;332(6035):1317-22. doi: 10.1126/science.1199498.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21659604" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; GRB10 Adaptor Protein/*metabolism ; Humans ; Insulin/metabolism ; Intercellular Signaling Peptides and Proteins/*metabolism ; Mass Spectrometry ; Mice ; Multiprotein Complexes ; Naphthyridines/pharmacology ; Phosphoproteins/metabolism ; Phosphorylation ; Proteins/*metabolism ; Proteome/metabolism ; *Signal Transduction ; Sirolimus/pharmacology ; TOR Serine-Threonine Kinases/*metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 8
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    mTORC1 phosphorylation sites encode their sensitivity to starvation and rapamycin (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-07-28
    Description: The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) protein kinase promotes growth and is the target of rapamycin, a clinically useful drug that also prolongs life span in model organisms. A persistent mystery is why the phosphorylation of many bona fide mTORC1 substrates is resistant to rapamycin. We find that the in vitro kinase activity of mTORC1 toward peptides encompassing established phosphorylation sites varies widely and correlates strongly with the resistance of the sites to rapamycin, as well as to nutrient and growth factor starvation within cells. Slight modifications of the sites were sufficient to alter mTORC1 activity toward them in vitro and to cause concomitant changes within cells in their sensitivity to rapamycin and starvation. Thus, the intrinsic capacity of a phosphorylation site to serve as an mTORC1 substrate, a property we call substrate quality, is a major determinant of its sensitivity to modulators of the pathway. Our results reveal a mechanism through which mTORC1 effectors can respond differentially to the same signals.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3771538/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3771538/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kang, Seong A -- Pacold, Michael E -- Cervantes, Christopher L -- Lim, Daniel -- Lou, Hua Jane -- Ottina, Kathleen -- Gray, Nathanael S -- Turk, Benjamin E -- Yaffe, Michael B -- Sabatini, David M -- AI047389/AI/NIAID NIH HHS/ -- CA103866/CA/NCI NIH HHS/ -- CA112967/CA/NCI NIH HHS/ -- ES015339/ES/NIEHS NIH HHS/ -- GM59281/GM/NIGMS NIH HHS/ -- P30 CA014051/CA/NCI NIH HHS/ -- R01 CA103866/CA/NCI NIH HHS/ -- R01 CA129105/CA/NCI NIH HHS/ -- R37 AI047389/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2013 Jul 26;341(6144):1236566. doi: 10.1126/science.1236566.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23888043" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acids/metabolism ; Animals ; Cell Line ; Culture Media ; Humans ; Mice ; Multiprotein Complexes ; Naphthyridines/pharmacology ; Peptides/chemistry/*metabolism ; Phosphorylation ; Proteins/antagonists & inhibitors/*chemistry/*metabolism ; Sirolimus/*pharmacology ; TOR Serine-Threonine Kinases/antagonists & inhibitors/*chemistry/*metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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