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  • 1
    Abstract: MYC oncoproteins are involved in the genesis and maintenance of the majority of human tumors but are considered undruggable. By using a direct in vivo shRNA screen, we show that liver cancer cells that have mutations in the gene encoding the tumor suppressor protein p53 (Trp53 in mice and TP53 in humans) and that are driven by the oncoprotein NRAS become addicted to MYC stabilization via a mechanism mediated by aurora kinase A (AURKA). This MYC stabilization enables the tumor cells to overcome a latent G2/M cell cycle arrest that is mediated by AURKA and the tumor suppressor protein p19(ARF). MYC directly binds to AURKA, and inhibition of this protein-protein interaction by conformation-changing AURKA inhibitors results in subsequent MYC degradation and cell death. These conformation-changing AURKA inhibitors, with one of them currently being tested in early clinical trials, suppressed tumor growth and prolonged survival in mice bearing Trp53-deficient, NRAS-driven MYC-expressing hepatocellular carcinomas (HCCs). TP53-mutated human HCCs revealed increased AURKA expression and a positive correlation between AURKA and MYC expression. In xenograft models, mice bearing TP53-mutated or TP53-deleted human HCCs were hypersensitive to treatment with conformation-changing AURKA inhibitors, thus suggesting a therapeutic strategy for this subgroup of human HCCs.
    Type of Publication: Journal article published
    PubMed ID: 27213815
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  • 2
    Keywords: PATHWAYS ; GENES ; STRATEGIES ; sensitivity ; MAP KINASES ; INTEGRATION ; KINASE INHIBITORS ; senescence ; ADVANCED HEPATOCELLULAR-CARCINOMA ; JAK/STAT
    Abstract: In solid tumors, resistance to therapy inevitably develops upon treatment with cytotoxic drugs or molecularly targeted therapies. Here, we describe a system that enables pooled shRNA screening directly in mouse hepatocellular carcinomas (HCC) in vivo to identify genes likely to be involved in therapy resistance. Using a focused shRNA library targeting genes located within focal genomic amplifications of human HCC, we screened for genes whose inhibition increased the therapeutic efficacy of the multikinase inhibitor sorafenib. Both shRNA-mediated and pharmacological silencing of Mapk14 (p38alpha) were found to sensitize mouse HCC to sorafenib therapy and prolong survival by abrogating Mapk14-dependent activation of Mek-Erk and Atf2 signaling. Elevated Mapk14-Atf2 signaling predicted poor response to sorafenib therapy in human HCC, and sorafenib resistance of p-Mapk14-expressing HCC cells could be reverted by silencing Mapk14. Our results suggest that a combination of sorafenib and Mapk14 blockade is a promising approach to overcoming therapy resistance of human HCC.
    Type of Publication: Journal article published
    PubMed ID: 25216638
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  • 3
    Publication Date: 2011-11-15
    Description: Upon the aberrant activation of oncogenes, normal cells can enter the cellular senescence program, a state of stable cell-cycle arrest, which represents an important barrier against tumour development in vivo. Senescent cells communicate with their environment by secreting various cytokines and growth factors, and it was reported that this 'secretory phenotype' can have pro- as well as anti-tumorigenic effects. Here we show that oncogene-induced senescence occurs in otherwise normal murine hepatocytes in vivo. Pre-malignant senescent hepatocytes secrete chemo- and cytokines and are subject to immune-mediated clearance (designated as 'senescence surveillance'), which depends on an intact CD4(+) T-cell-mediated adaptive immune response. Impaired immune surveillance of pre-malignant senescent hepatocytes results in the development of murine hepatocellular carcinomas (HCCs), thus showing that senescence surveillance is important for tumour suppression in vivo. In accordance with these observations, ras-specific Th1 lymphocytes could be detected in mice, in which oncogene-induced senescence had been triggered by hepatic expression of Nras(G12V). We also found that CD4(+) T cells require monocytes/macrophages to execute the clearance of senescent hepatocytes. Our study indicates that senescence surveillance represents an important extrinsic component of the senescence anti-tumour barrier, and illustrates how the cellular senescence program is involved in tumour immune surveillance by mounting specific immune responses against antigens expressed in pre-malignant senescent cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kang, Tae-Won -- Yevsa, Tetyana -- Woller, Norman -- Hoenicke, Lisa -- Wuestefeld, Torsten -- Dauch, Daniel -- Hohmeyer, Anja -- Gereke, Marcus -- Rudalska, Ramona -- Potapova, Anna -- Iken, Marcus -- Vucur, Mihael -- Weiss, Siegfried -- Heikenwalder, Mathias -- Khan, Sadaf -- Gil, Jesus -- Bruder, Dunja -- Manns, Michael -- Schirmacher, Peter -- Tacke, Frank -- Ott, Michael -- Luedde, Tom -- Longerich, Thomas -- Kubicka, Stefan -- Zender, Lars -- MC_U120085810/Medical Research Council/United Kingdom -- England -- Nature. 2011 Nov 9;479(7374):547-51. doi: 10.1038/nature10599.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22080947" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, Neoplasm/immunology ; CD4-Positive T-Lymphocytes/immunology ; Cancer Vaccines/immunology ; Carcinoma, Hepatocellular/genetics/immunology/pathology/prevention & control ; Cell Aging/genetics/*immunology ; Disease Progression ; Genes, ras/genetics ; Hepatocytes/cytology/*immunology/metabolism/pathology ; Humans ; Immunologic Surveillance/*immunology ; Liver/cytology/immunology ; Liver Neoplasms/genetics/*immunology/*pathology/prevention & control ; Mice ; Mice, SCID ; Phagocytosis ; Precancerous Conditions/genetics/*immunology/*pathology/prevention & control
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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