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      A MYC-aurora kinase A protein complex represents an actionable drug target in p53-altered liver cancer.

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          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.

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          Author and article information

          Journal
          Nat. Med.
          Nature medicine
          Springer Nature
          1546-170X
          1078-8956
          Jul 2016
          : 22
          : 7
          Affiliations
          [1 ] Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, University of Tuebingen, Tuebingen, Germany.
          [2 ] Theodor Boveri Institute, Biocenter, University of Wuerzburg, Wuerzburg, Germany.
          [3 ] Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.
          [4 ] Translational Gastrointestinal Oncology Group within the German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
          [5 ] School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
          [6 ] Department of Internal Medicine I, University of Tuebingen, Tuebingen, Germany.
          [7 ] Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany.
          [8 ] Department of Pharmaceutical Chemistry, University of Tuebingen, Tuebingen, Germany.
          [9 ] Comprehensive Cancer Center Mainfranken, University of Wuerzburg, Wuerzburg, Germany.
          Article
          nm.4107
          10.1038/nm.4107
          27213815

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