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MCL-1 gains occur with high frequency in lung adenocarcinoma and can be targeted therapeutically

Author

Listed:
  • Enkhtsetseg Munkhbaatar

    (Technical University of Munich)

  • Michelle Dietzen

    (University College London Cancer Institute
    Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute
    University College London Cancer Institute, University College London)

  • Deepti Agrawal

    (Technical University of Munich)

  • Martina Anton

    (Technical University of Munich)

  • Moritz Jesinghaus

    (Technical University of Munich)

  • Melanie Boxberg

    (Technical University of Munich)

  • Nicole Pfarr

    (Technical University of Munich)

  • Pidassa Bidola

    (Technical University of Munich)

  • Sebastian Uhrig

    (Division of Applied Bioinformatics, German Cancer Research Center
    Faculty of Biosciences, Heidelberg University)

  • Ulrike Höckendorf

    (Technical University of Munich)

  • Anna-Lena Meinhardt

    (Technical University of Munich)

  • Adam Wahida

    (Technical University of Munich)

  • Irina Heid

    (Technical University of Munich)

  • Rickmer Braren

    (Technical University of Munich)

  • Ritu Mishra

    (Technical University of Munich)

  • Arne Warth

    (University Hospital Heidelberg
    Institute of Pathology, Cytopathology and Molecular Pathology UEGP MVZ)

  • Thomas Muley

    (Thoraxklinik at Heidelberg University
    Translational Lung Research Centre (TLRC) Heidelberg, member of the German Centre for lung Research (DZL))

  • Patrina S. P. Poh

    (Technical University of Munich
    Julius Wolff Institute, Charité - Universitätsmedizin Berlin)

  • Xin Wang

    (Technical University of Munich)

  • Stefan Fröhling

    (Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ)
    German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ))

  • Katja Steiger

    (Technical University of Munich
    German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ))

  • Julia Slotta-Huspenina

    (Technical University of Munich
    Gewebebank des Klinikums rechts der Isar und der Technischen Universität München Am Institut für Pathologie der TU München)

  • Martijn van Griensven

    (Maastricht University)

  • Franz Pfeiffer

    (Technical University of Munich)

  • Sebastian Lange

    (Technical University of Munich
    Technical University of Munich
    Technical University of Munich)

  • Roland Rad

    (Technical University of Munich
    German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
    Technical University of Munich
    Technical University of Munich)

  • Magda Spella

    (University of Patras)

  • Georgios T. Stathopoulos

    (Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD), Helmholtz Center Munich for Environmental Health, Member of the German Center for Lung Research (DZL))

  • Jürgen Ruland

    (German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
    Technical University of Munich)

  • Florian Bassermann

    (Technical University of Munich
    Technical University of Munich
    German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ))

  • Wilko Weichert

    (Technical University of Munich
    German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ))

  • Andreas Strasser

    (The Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Caterina Branca

    (Technical University of Munich)

  • Mathias Heikenwalder

    (Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ))

  • Charles Swanton

    (University College London Cancer Institute
    Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute)

  • Nicholas McGranahan

    (University College London Cancer Institute
    University College London Cancer Institute, University College London)

  • Philipp J. Jost

    (Technical University of Munich
    Technical University of Munich
    German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)
    Medical University of Graz)

Abstract

Evasion of programmed cell death represents a critical form of oncogene addiction in cancer cells. Understanding the molecular mechanisms underpinning cancer cell survival despite the oncogenic stress could provide a molecular basis for potential therapeutic interventions. Here we explore the role of pro-survival genes in cancer cell integrity during clonal evolution in non-small cell lung cancer (NSCLC). We identify gains of MCL-1 at high frequency in multiple independent NSCLC cohorts, occurring both clonally and subclonally. Clonal loss of functional TP53 is significantly associated with subclonal gains of MCL-1. In mice, tumour progression is delayed upon pharmacologic or genetic inhibition of MCL-1. These findings reveal that MCL-1 gains occur with high frequency in lung adenocarcinoma and can be targeted therapeutically.

Suggested Citation

  • Enkhtsetseg Munkhbaatar & Michelle Dietzen & Deepti Agrawal & Martina Anton & Moritz Jesinghaus & Melanie Boxberg & Nicole Pfarr & Pidassa Bidola & Sebastian Uhrig & Ulrike Höckendorf & Anna-Lena Mein, 2020. "MCL-1 gains occur with high frequency in lung adenocarcinoma and can be targeted therapeutically," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18372-1
    DOI: 10.1038/s41467-020-18372-1
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