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

Nature Medicine volume 22, pages 744–753 (2016)Cite this article

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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 p19ARF. 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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Figure 1: Trp53-deficient hepatocytes undergo a G2/M cell cycle arrest after activation of RAS–MAPK signaling.
Figure 2: In vivo RNAi screening identifies an AURKA-dependent G2/M arrest in Trp53−/− hepatocytes.
Figure 3: MYC induction during liver regeneration allows NrasG12V; Trp53−/− hepatocytes to bypass a G2/M cell cycle arrest.
Figure 4: AURKA stabilizes MYC by a protein–protein interaction in Trp53−/− HCCs.
Figure 5: Conformation-changing AURKA inhibitors prohibit the formation of p-MYC–AURKA protein complexes.
Figure 6: TP53-altered human HCCs show marked treatment responses toward the AURKA inhibitor MLN8237.

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Acknowledgements

We thank K. Schulze-Osthoff, S.W. Lowe, W. Albrecht, K. Breuhahn, R. Geffers, S. Nahnsen, M. Gehringer, E. Rist, C. Fellmeth, P. Katiyar, S. Fillinger, M. Jarek, M. Scharfe, M. Diefenbacher and the members of the Zender laboratory for fruitful discussions, technical assistance or reagents. We thank the Center for Scientific Computing (Espoo, Finland) for software and hardware support. This work was supported by the German Research Foundation (DFG; grants FOR2314 (L.Z., D.D. and M.E.) and SFB685 (L.Z.)), the Gottfried Wilhelm Leibniz Program (L.Z.), the European Research Council (projects 'CholangioConcept' (L.Z.), 'Heptromic' (L.Z.) and 'Auromyc' (M.E.)), the German Ministry for Education and Research (BMBF) (eMed (Multiscale HCC), the German Universities Excellence Initiative (third funding line: 'future concept') (L.Z.), the German Center for Translational Cancer Research (DKTK) (L.Z.) and the German–Israeli Cooperation in Cancer Research (DKFZ–MOST) (L.Z.).

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Authors and Affiliations

  1. Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, University of Tuebingen, Tuebingen, Germany

    Daniel Dauch, Ramona Rudalska, Tae-Won Kang, Torsten Wuestefeld, Anja Hohmeyer, Tetyana Yevsa, Lisa Hoenicke, Antti Poso & Lars Zender

  2. Theodor Boveri Institute, Biocenter, University of Wuerzburg, Wuerzburg, Germany

    Giacomo Cossa & Martin Eilers

  3. Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France

    Jean-Charles Nault, Sandrine Imbeaud & Jessica Zucman-Rossi

  4. Translational Gastrointestinal Oncology Group within the German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

    Tae-Won Kang & Lars Zender

  5. School of Pharmacy, University of Eastern Finland, Kuopio, Finland

    Tatu Pantsar & Antti Poso

  6. Department of Internal Medicine I, University of Tuebingen, Tuebingen, Germany

    Przemyslaw Bozko & Nisar P Malek

  7. Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany

    Thomas Longerich

  8. Department of Pharmaceutical Chemistry, University of Tuebingen, Tuebingen, Germany

    Stefan Laufer

  9. Comprehensive Cancer Center Mainfranken, University of Wuerzburg, Wuerzburg, Germany

    Martin Eilers

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  1. Daniel Dauch
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Contributions

L.Z. and D.D. designed the study; D.D., R.R., G.C., T.-W.K., T.W., A.H., T.Y., L.H. and P.B. conducted the research; T.L. performed the histopathological analyses; J.-C.N., S.I., T.L. and J.Z.-R. collected and analyzed the human HCC samples; T.P. and A.P. performed the molecular modeling; N.P.M., S.L. and M.E. contributed to research design; and L.Z. and D.D wrote the manuscript.

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Correspondence to Lars Zender.

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Supplementary Table 1

mRNA Expression data (XLS 7070 kb)

Supplementary Table 2

Genes included in the shRNA library (XLS 36 kb)

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Dauch, D., Rudalska, R., Cossa, G. et al. A MYC–aurora kinase A protein complex represents an actionable drug target in p53-altered liver cancer. Nat Med 22, 744–753 (2016). https://doi.org/10.1038/nm.4107

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