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MYC paralog-dependent apoptotic priming orchestrates a spectrum of vulnerabilities in small cell lung cancer

Author

Listed:
  • Marcel A. Dammert

    (University Hospital of Cologne
    University of Cologne
    University of Cologne)

  • Johannes Brägelmann

    (University Hospital of Cologne
    University of Cologne
    University of Cologne
    University Hospital Cologne)

  • Rachelle R. Olsen

    (Huntsman Cancer Institute, University of Utah)

  • Stefanie Böhm

    (University of Cologne
    University of Cologne)

  • Niloufar Monhasery

    (University Hospital of Cologne
    University of Cologne
    University of Cologne)

  • Christopher P. Whitney

    (Huntsman Cancer Institute, University of Utah)

  • Milind D. Chalishazar

    (Huntsman Cancer Institute, University of Utah)

  • Hannah L. Tumbrink

    (University Hospital of Cologne
    University of Cologne
    University of Cologne)

  • Matthew R. Guthrie

    (Huntsman Cancer Institute, University of Utah)

  • Sebastian Klein

    (University of Cologne
    University of Cologne
    University Hospital Cologne
    University Hospital of Cologne)

  • Abbie S. Ireland

    (Huntsman Cancer Institute, University of Utah)

  • Jeremy Ryan

    (Harvard Medical School)

  • Anna Schmitt

    (University Hospital of Cologne
    University of Cologne)

  • Annika Marx

    (University Hospital of Cologne
    University of Cologne
    University of Cologne)

  • Luka Ozretić

    (Royal Free Hospital)

  • Roberta Castiglione

    (University Hospital Cologne
    University Hospital of Cologne)

  • Carina Lorenz

    (University Hospital of Cologne
    University of Cologne
    University of Cologne)

  • Ron D. Jachimowicz

    (University Hospital of Cologne
    University of Cologne)

  • Elmar Wolf

    (University of Würzburg)

  • Roman K. Thomas

    (University of Cologne)

  • John T. Poirier

    (Memorial Sloan Kettering Cancer Center)

  • Reinhard Büttner

    (University Hospital of Cologne)

  • Triparna Sen

    (University of Texas, MD Anderson Cancer Center)

  • Lauren A. Byers

    (University of Texas, MD Anderson Cancer Center)

  • H. Christian Reinhardt

    (University Hospital Cologne
    University Hospital of Cologne
    University of Cologne)

  • Anthony Letai

    (Harvard Medical School)

  • Trudy G. Oliver

    (Huntsman Cancer Institute, University of Utah)

  • Martin L. Sos

    (University Hospital of Cologne
    University of Cologne
    University of Cologne)

Abstract

MYC paralogs are frequently activated in small cell lung cancer (SCLC) but represent poor drug targets. Thus, a detailed mapping of MYC-paralog-specific vulnerabilities may help to develop effective therapies for SCLC patients. Using a unique cellular CRISPR activation model, we uncover that, in contrast to MYCN and MYCL, MYC represses BCL2 transcription via interaction with MIZ1 and DNMT3a. The resulting lack of BCL2 expression promotes sensitivity to cell cycle control inhibition and dependency on MCL1. Furthermore, MYC activation leads to heightened apoptotic priming, intrinsic genotoxic stress and susceptibility to DNA damage checkpoint inhibitors. Finally, combined AURK and CHK1 inhibition substantially prolongs the survival of mice bearing MYC-driven SCLC beyond that of combination chemotherapy. These analyses uncover MYC-paralog-specific regulation of the apoptotic machinery with implications for genotype-based selection of targeted therapeutics in SCLC patients.

Suggested Citation

  • Marcel A. Dammert & Johannes Brägelmann & Rachelle R. Olsen & Stefanie Böhm & Niloufar Monhasery & Christopher P. Whitney & Milind D. Chalishazar & Hannah L. Tumbrink & Matthew R. Guthrie & Sebastian , 2019. "MYC paralog-dependent apoptotic priming orchestrates a spectrum of vulnerabilities in small cell lung cancer," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11371-x
    DOI: 10.1038/s41467-019-11371-x
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    Cited by:

    1. Jonuelle Acosta & Qinglan Li & Nelson F. Freeburg & Nivitha Murali & Alexandra Indeglia & Grant P. Grothusen & Michelle Cicchini & Hung Mai & Amy C. Gladstein & Keren M. Adler & Katherine R. Doerig & , 2023. "p53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanism," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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