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

Enkhtsetseg Munkhbaatar, Michelle Dietzen, Deepti Agrawal, Martina Anton, Moritz Jesinghaus, Melanie Boxberg, Nicole Pfarr, Pidassa Bidola, Sebastian Uhrig, Ulrike Höckendorf, Anna-Lena Meinhardt, Adam Wahida, Irina Heid, Rickmer Braren, Ritu Mishra, Arne Warth, Thomas Muley, Patrina S. P. Poh, Xin Wang, Stefan Fröhling, Katja Steiger, Julia Slotta-Huspenina, Martijn van Griensven, Franz Pfeiffer, Sebastian Lange, Roland Rad, Magda Spella, Georgios T. Stathopoulos, Jürgen Ruland, Florian Bassermann, Wilko Weichert, Andreas Strasser, Caterina Branca, Mathias Heikenwalder, Charles Swanton, Nicholas McGranahan and Philipp J. Jost ()
Additional contact information
Enkhtsetseg Munkhbaatar: Technical University of Munich
Michelle Dietzen: University College London Cancer Institute
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
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
Thomas Muley: Thoraxklinik at Heidelberg University
Patrina S. P. Poh: Technical University of Munich
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)
Katja Steiger: Technical University of Munich
Julia Slotta-Huspenina: Technical University of Munich
Martijn van Griensven: Maastricht University
Franz Pfeiffer: Technical University of Munich
Sebastian Lange: Technical University of Munich
Roland Rad: 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)
Florian Bassermann: Technical University of Munich
Wilko Weichert: Technical University of Munich
Andreas Strasser: The Walter and Eliza Hall Institute of Medical Research
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
Nicholas McGranahan: University College London Cancer Institute
Philipp J. Jost: Technical University of Munich

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18372-1

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