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  • Mutation/*genetics  (2)
  • Mutation/genetics  (2)
  • Nature Publishing Group (NPG)  (4)
  • 1
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    RAF inhibitors that evade paradoxical MAPK pathway activation (2015)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2015-10-16
    Description: Oncogenic activation of BRAF fuels cancer growth by constitutively promoting RAS-independent mitogen-activated protein kinase (MAPK) pathway signalling. Accordingly, RAF inhibitors have brought substantially improved personalized treatment of metastatic melanoma. However, these targeted agents have also revealed an unexpected consequence: stimulated growth of certain cancers. Structurally diverse ATP-competitive RAF inhibitors can either inhibit or paradoxically activate the MAPK pathway, depending whether activation is by BRAF mutation or by an upstream event, such as RAS mutation or receptor tyrosine kinase activation. Here we have identified next-generation RAF inhibitors (dubbed 'paradox breakers') that suppress mutant BRAF cells without activating the MAPK pathway in cells bearing upstream activation. In cells that express the same HRAS mutation prevalent in squamous tumours from patients treated with RAF inhibitors, the first-generation RAF inhibitor vemurafenib stimulated in vitro and in vivo growth and induced expression of MAPK pathway response genes; by contrast the paradox breakers PLX7904 and PLX8394 had no effect. Paradox breakers also overcame several known mechanisms of resistance to first-generation RAF inhibitors. Dissociating MAPK pathway inhibition from paradoxical activation might yield both improved safety and more durable efficacy than first-generation RAF inhibitors, a concept currently undergoing human clinical evaluation with PLX8394.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Chao -- Spevak, Wayne -- Zhang, Ying -- Burton, Elizabeth A -- Ma, Yan -- Habets, Gaston -- Zhang, Jiazhong -- Lin, Jack -- Ewing, Todd -- Matusow, Bernice -- Tsang, Garson -- Marimuthu, Adhirai -- Cho, Hanna -- Wu, Guoxian -- Wang, Weiru -- Fong, Daniel -- Nguyen, Hoa -- Shi, Songyuan -- Womack, Patrick -- Nespi, Marika -- Shellooe, Rafe -- Carias, Heidi -- Powell, Ben -- Light, Emily -- Sanftner, Laura -- Walters, Jason -- Tsai, James -- West, Brian L -- Visor, Gary -- Rezaei, Hamid -- Lin, Paul S -- Nolop, Keith -- Ibrahim, Prabha N -- Hirth, Peter -- Bollag, Gideon -- England -- Nature. 2015 Oct 22;526(7574):583-6. doi: 10.1038/nature14982. Epub 2015 Oct 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26466569" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line, Tumor ; Enzyme Activation/drug effects ; Female ; Genes, ras/genetics ; Heterocyclic Compounds, 2-Ring/adverse effects/pharmacology ; Humans ; Indoles/adverse effects/pharmacology ; MAP Kinase Signaling System/*drug effects/genetics ; Mice ; Mitogen-Activated Protein Kinases/*metabolism ; Models, Biological ; Mutation/genetics ; Protein Kinase Inhibitors/adverse effects/*pharmacology ; Proto-Oncogene Proteins B-raf/*antagonists & inhibitors/genetics ; Sulfonamides/adverse effects/pharmacology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    The genetic basis of early T-cell precursor acute lymphoblastic leukaemia (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-01-13
    Description: Early T-cell precursor acute lymphoblastic leukaemia (ETP ALL) is an aggressive malignancy of unknown genetic basis. We performed whole-genome sequencing of 12 ETP ALL cases and assessed the frequency of the identified somatic mutations in 94 T-cell acute lymphoblastic leukaemia cases. ETP ALL was characterized by activating mutations in genes regulating cytokine receptor and RAS signalling (67% of cases; NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF), inactivating lesions disrupting haematopoietic development (58%; GATA3, ETV6, RUNX1, IKZF1 and EP300) and histone-modifying genes (48%; EZH2, EED, SUZ12, SETD2 and EP300). We also identified new targets of recurrent mutation including DNM2, ECT2L and RELN. The mutational spectrum is similar to myeloid tumours, and moreover, the global transcriptional profile of ETP ALL was similar to that of normal and myeloid leukaemia haematopoietic stem cells. These findings suggest that addition of myeloid-directed therapies might improve the poor outcome of ETP ALL.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3267575/" 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/PMC3267575/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Jinghui -- Ding, Li -- Holmfeldt, Linda -- Wu, Gang -- Heatley, Sue L -- Payne-Turner, Debbie -- Easton, John -- Chen, Xiang -- Wang, Jianmin -- Rusch, Michael -- Lu, Charles -- Chen, Shann-Ching -- Wei, Lei -- Collins-Underwood, J Racquel -- Ma, Jing -- Roberts, Kathryn G -- Pounds, Stanley B -- Ulyanov, Anatoly -- Becksfort, Jared -- Gupta, Pankaj -- Huether, Robert -- Kriwacki, Richard W -- Parker, Matthew -- McGoldrick, Daniel J -- Zhao, David -- Alford, Daniel -- Espy, Stephen -- Bobba, Kiran Chand -- Song, Guangchun -- Pei, Deqing -- Cheng, Cheng -- Roberts, Stefan -- Barbato, Michael I -- Campana, Dario -- Coustan-Smith, Elaine -- Shurtleff, Sheila A -- Raimondi, Susana C -- Kleppe, Maria -- Cools, Jan -- Shimano, Kristin A -- Hermiston, Michelle L -- Doulatov, Sergei -- Eppert, Kolja -- Laurenti, Elisa -- Notta, Faiyaz -- Dick, John E -- Basso, Giuseppe -- Hunger, Stephen P -- Loh, Mignon L -- Devidas, Meenakshi -- Wood, Brent -- Winter, Stuart -- Dunsmore, Kimberley P -- Fulton, Robert S -- Fulton, Lucinda L -- Hong, Xin -- Harris, Christopher C -- Dooling, David J -- Ochoa, Kerri -- Johnson, Kimberly J -- Obenauer, John C -- Evans, William E -- Pui, Ching-Hon -- Naeve, Clayton W -- Ley, Timothy J -- Mardis, Elaine R -- Wilson, Richard K -- Downing, James R -- Mullighan, Charles G -- CA114766/CA/NCI NIH HHS/ -- CA98413/CA/NCI NIH HHS/ -- CA98543/CA/NCI NIH HHS/ -- P30 CA021765/CA/NCI NIH HHS/ -- P30 CA021765-33/CA/NCI NIH HHS/ -- P30CA021765/CA/NCI NIH HHS/ -- U01GM92666/GM/NIGMS NIH HHS/ -- U54 HG003079/HG/NHGRI NIH HHS/ -- England -- Nature. 2012 Jan 11;481(7380):157-63. doi: 10.1038/nature10725.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Computational Biology and Bioinformatics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22237106" target="_blank"〉PubMed〈/a〉
    Keywords: Age of Onset ; Child ; DNA Copy Number Variations/genetics ; Genes, ras/genetics ; Genetic Predisposition to Disease/*genetics ; Genome, Human/genetics ; Genomics ; Hematopoiesis/genetics ; Histones/metabolism ; Humans ; Janus Kinases/genetics/metabolism ; Leukemia, Myeloid, Acute/drug therapy/genetics/pathology ; Molecular Sequence Data ; Mutation/*genetics ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/*genetics/pathology ; Receptors, Interleukin-7/genetics ; Sequence Analysis, DNA ; Signal Transduction/genetics ; Stem Cells/metabolism/pathology ; T-Lymphocytes/metabolism/pathology ; Translocation, Genetic/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    A novel retinoblastoma therapy from genomic and epigenetic analyses (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-01-13
    Description: Retinoblastoma is an aggressive childhood cancer of the developing retina that is initiated by the biallelic loss of RB1. Tumours progress very quickly following RB1 inactivation but the underlying mechanism is not known. Here we show that the retinoblastoma genome is stable, but that multiple cancer pathways can be epigenetically deregulated. To identify the mutations that cooperate with RB1 loss, we performed whole-genome sequencing of retinoblastomas. The overall mutational rate was very low; RB1 was the only known cancer gene mutated. We then evaluated the role of RB1 in genome stability and considered non-genetic mechanisms of cancer pathway deregulation. For example, the proto-oncogene SYK is upregulated in retinoblastoma and is required for tumour cell survival. Targeting SYK with a small-molecule inhibitor induced retinoblastoma tumour cell death in vitro and in vivo. Thus, retinoblastomas may develop quickly as a result of the epigenetic deregulation of key cancer pathways as a direct or indirect result of RB1 loss.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3289956/" 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/PMC3289956/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Jinghui -- Benavente, Claudia A -- McEvoy, Justina -- Flores-Otero, Jacqueline -- Ding, Li -- Chen, Xiang -- Ulyanov, Anatoly -- Wu, Gang -- Wilson, Matthew -- Wang, Jianmin -- Brennan, Rachel -- Rusch, Michael -- Manning, Amity L -- Ma, Jing -- Easton, John -- Shurtleff, Sheila -- Mullighan, Charles -- Pounds, Stanley -- Mukatira, Suraj -- Gupta, Pankaj -- Neale, Geoff -- Zhao, David -- Lu, Charles -- Fulton, Robert S -- Fulton, Lucinda L -- Hong, Xin -- Dooling, David J -- Ochoa, Kerri -- Naeve, Clayton -- Dyson, Nicholas J -- Mardis, Elaine R -- Bahrami, Armita -- Ellison, David -- Wilson, Richard K -- Downing, James R -- Dyer, Michael A -- CA21765/CA/NCI NIH HHS/ -- CA64402/CA/NCI NIH HHS/ -- EY014867/EY/NEI NIH HHS/ -- EY018599/EY/NEI NIH HHS/ -- GM81607/GM/NIGMS NIH HHS/ -- R01 CA155202/CA/NCI NIH HHS/ -- R01 EY014867/EY/NEI NIH HHS/ -- R01 EY014867-02/EY/NEI NIH HHS/ -- R01 EY018599/EY/NEI NIH HHS/ -- R01 EY018599-03/EY/NEI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Jan 11;481(7381):329-34. doi: 10.1038/nature10733.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Computational Biology and Bioinformatics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22237022" target="_blank"〉PubMed〈/a〉
    Keywords: Aneuploidy ; Animals ; Cell Death/drug effects ; Cell Line ; Cell Survival/drug effects ; Chromosomal Instability/genetics ; Epigenesis, Genetic/*genetics ; Gene Expression Regulation, Neoplastic ; Genes, Retinoblastoma/genetics ; *Genomics ; Humans ; Intracellular Signaling Peptides and Proteins/antagonists & ; inhibitors/genetics/metabolism ; Mice ; *Molecular Targeted Therapy ; Mutation/genetics ; Protein Kinase Inhibitors/*pharmacology/therapeutic use ; Protein-Tyrosine Kinases/antagonists & inhibitors/genetics/metabolism ; Retinoblastoma/*drug therapy/*genetics/pathology ; Retinoblastoma Protein/deficiency/genetics ; Sequence Analysis, DNA ; Xenograft Model Antitumor Assays
    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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    Novel mutations target distinct subgroups of medulloblastoma (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-06-23
    Description: Medulloblastoma is a malignant childhood brain tumour comprising four discrete subgroups. Here, to identify mutations that drive medulloblastoma, we sequenced the entire genomes of 37 tumours and matched normal blood. One-hundred and thirty-six genes harbouring somatic mutations in this discovery set were sequenced in an additional 56 medulloblastomas. Recurrent mutations were detected in 41 genes not yet implicated in medulloblastoma; several target distinct components of the epigenetic machinery in different disease subgroups, such as regulators of H3K27 and H3K4 trimethylation in subgroups 3 and 4 (for example, KDM6A and ZMYM3), and CTNNB1-associated chromatin re-modellers in WNT-subgroup tumours (for example, SMARCA4 and CREBBP). Modelling of mutations in mouse lower rhombic lip progenitors that generate WNT-subgroup tumours identified genes that maintain this cell lineage (DDX3X), as well as mutated genes that initiate (CDH1) or cooperate (PIK3CA) in tumorigenesis. These data provide important new insights into the pathogenesis of medulloblastoma subgroups and highlight targets for therapeutic development.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3412905/" 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/PMC3412905/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Robinson, Giles -- Parker, Matthew -- Kranenburg, Tanya A -- Lu, Charles -- Chen, Xiang -- Ding, Li -- Phoenix, Timothy N -- Hedlund, Erin -- Wei, Lei -- Zhu, Xiaoyan -- Chalhoub, Nader -- Baker, Suzanne J -- Huether, Robert -- Kriwacki, Richard -- Curley, Natasha -- Thiruvenkatam, Radhika -- Wang, Jianmin -- Wu, Gang -- Rusch, Michael -- Hong, Xin -- Becksfort, Jared -- Gupta, Pankaj -- Ma, Jing -- Easton, John -- Vadodaria, Bhavin -- Onar-Thomas, Arzu -- Lin, Tong -- Li, Shaoyi -- Pounds, Stanley -- Paugh, Steven -- Zhao, David -- Kawauchi, Daisuke -- Roussel, Martine F -- Finkelstein, David -- Ellison, David W -- Lau, Ching C -- Bouffet, Eric -- Hassall, Tim -- Gururangan, Sridharan -- Cohn, Richard -- Fulton, Robert S -- Fulton, Lucinda L -- Dooling, David J -- Ochoa, Kerri -- Gajjar, Amar -- Mardis, Elaine R -- Wilson, Richard K -- Downing, James R -- Zhang, Jinghui -- Gilbertson, Richard J -- P01 CA096832/CA/NCI NIH HHS/ -- P01CA96832/CA/NCI NIH HHS/ -- P30 CA021765/CA/NCI NIH HHS/ -- P30CA021765/CA/NCI NIH HHS/ -- R01 CA129541/CA/NCI NIH HHS/ -- R01CA129541/CA/NCI NIH HHS/ -- England -- Nature. 2012 Aug 2;488(7409):43-8. doi: 10.1038/nature11213.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉St Jude Children's Research Hospital, Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22722829" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; CREB-Binding Protein/genetics ; Cadherins/genetics ; Cdh1 Proteins ; Cell Cycle Proteins/deficiency/genetics ; Cell Lineage ; Cerebellar Neoplasms/*classification/*genetics/pathology ; Child ; DEAD-box RNA Helicases/genetics ; DNA Copy Number Variations ; DNA Helicases/genetics ; DNA Mutational Analysis ; Disease Models, Animal ; Genome, Human/genetics ; Genomics ; Hedgehog Proteins/metabolism ; Histone Demethylases/genetics ; Histones/metabolism ; Humans ; Medulloblastoma/*classification/*genetics/pathology ; Methylation ; Mice ; Mutation/*genetics ; Nuclear Proteins/genetics ; Phosphatidylinositol 3-Kinases/genetics ; Transcription Factors/genetics ; Wnt Proteins/metabolism ; beta Catenin/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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