title: A MYC-aurora kinase A protein complex represents an actionable drug target in p53-altered liver cancer.
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.
authors.affiliation: Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, University of Tuebingen, Tuebingen, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Dauch
authors.affiliation: Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, University of Tuebingen, Tuebingen, Germany.
authors.forename: Ramona
authors.initials: R
authors.lastname: Rudalska
authors.affiliation: Theodor Boveri Institute, Biocenter, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Cossa
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Nault
authors.affiliation: Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, University of Tuebingen, Tuebingen, Germany.|Translational Gastrointestinal Oncology Group within the German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Tae-Won
authors.initials: TW
authors.lastname: Kang
authors.affiliation: Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, University of Tuebingen, Tuebingen, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Wuestefeld
authors.affiliation: Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, University of Tuebingen, Tuebingen, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Hohmeyer
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Imbeaud
authors.affiliation: Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, University of Tuebingen, Tuebingen, Germany.
authors.forename: Tetyana
authors.initials: T
authors.lastname: Yevsa
authors.affiliation: Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, University of Tuebingen, Tuebingen, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Hoenicke
authors.affiliation: School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
authors.forename: Tatu
authors.initials: T
authors.lastname: Pantsar
authors.affiliation: Department of Internal Medicine I, University of Tuebingen, Tuebingen, Germany.
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Bozko
authors.affiliation: Department of Internal Medicine I, University of Tuebingen, Tuebingen, Germany.
authors.forename: Nisar P
authors.initials: NP
authors.lastname: Malek
authors.affiliation: Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Longerich
authors.affiliation: Department of Pharmaceutical Chemistry, University of Tuebingen, Tuebingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Laufer
authors.affiliation: Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, University of Tuebingen, Tuebingen, Germany.|School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
authors.forename: Antti
authors.initials: A
authors.lastname: Poso
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.
authors.forename: Jessica
authors.identifier: 0000-0002-5687-0334
authors.initials: J
authors.lastname: Zucman-Rossi
authors.affiliation: Theodor Boveri Institute, Biocenter, University of Wuerzburg, Wuerzburg, Germany.|Comprehensive Cancer Center Mainfranken, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Martin
authors.identifier: 0000-0002-0376-6533
authors.initials: M
authors.lastname: Eilers
authors.affiliation: Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, University of Tuebingen, Tuebingen, Germany.|Translational Gastrointestinal Oncology Group within the German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Zender
mesh_terms: D000818:Animals; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001381:Azepines / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D017353:Gene Deletion; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics*; D009154:Mutation; D015689:Oncogene Protein p21(ras) / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D001381:Azepines; C000592902:CD532 compound; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; C550258:MLN 8237; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D011743:Pyrimidines; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D064096:Aurora Kinase A; D020559:Monomeric GTP-Binding Proteins; C586503:Nras protein, mouse; D015689:Oncogene Protein p21(ras)