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; Philipp J Jost

doi:10.1038/s41467-020-18372-1

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

Nat Commun. 2020 Sep 10;11(1):4527. doi: 10.1038/s41467-020-18372-1.

Authors

Enkhtsetseg Munkhbaatar^#¹, Michelle Dietzen^#^{2

3

4}, Deepti Agrawal¹, Martina Anton⁵, Moritz Jesinghaus⁶, Melanie Boxberg⁶, Nicole Pfarr⁶, Pidassa Bidola⁷, Sebastian Uhrig^{8

9}, Ulrike Höckendorf¹, Anna-Lena Meinhardt¹, Adam Wahida¹, Irina Heid¹⁰, Rickmer Braren¹⁰, Ritu Mishra¹¹, Arne Warth^{12

13}, Thomas Muley^{14

15}, Patrina S P Poh^{16

17}, Xin Wang¹, Stefan Fröhling^{18

19}, Katja Steiger^{6

19}, Julia Slotta-Huspenina^{6

20}, Martijn van Griensven²¹, Franz Pfeiffer⁷, Sebastian Lange^{11

22

23}, Roland Rad^{11

19

22

23}, Magda Spella²⁴, Georgios T Stathopoulos²⁵, Jürgen Ruland^{19

26}, Florian Bassermann^{1

11

19}, Wilko Weichert^{6

19}, Andreas Strasser^{27

28}, Caterina Branca¹, Mathias Heikenwalder²⁹, Charles Swanton^{2

3}, Nicholas McGranahan^{2

4}, Philipp J Jost^{30

31

32

33}

Affiliations

¹ Department of Medicine III, Klinikum rechts der Isar, TUM School of Medicine, Technical University of Munich, Munich, Germany.
² Cancer Research UK Lung Cancer Center of Excellence, University College London Cancer Institute, Paul O'Gorman Building, London, UK.
³ Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK.
⁴ Cancer Genome Evolution Research Group, University College London Cancer Institute, University College London, London, UK.
⁵ Institute of Molecular Immunology and Experimental Oncology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
⁶ Institute of Pathology, Technical University of Munich, Munich, Germany.
⁷ Chair of Biomedical Physics, Department of Physics & Munich School of Bioengineering, Technical University of Munich, Garching, Germany.
⁸ Division of Applied Bioinformatics, German Cancer Research Center, Heidelberg, Germany.
⁹ Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
¹⁰ Department of diagnostic and interventional radiology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
¹¹ Center for Translational Cancer Research (TranslaTUM), Technical University of Munich, Munich, Germany.
¹² Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
¹³ Institute of Pathology, Cytopathology and Molecular Pathology UEGP MVZ, Giessen, Wetzlar, Limburg, Germany.
¹⁴ Translational Research Unit, Thoraxklinik at Heidelberg University, Heidelberg, Germany.
¹⁵ Translational Lung Research Centre (TLRC) Heidelberg, member of the German Centre for lung Research (DZL), Heidelberg, Germany.
¹⁶ Experimental Trauma Surgery, Department of Trauma Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
¹⁷ Julius Wolff Institute, Charité - Universitätsmedizin Berlin, Berlin, Germany.
¹⁸ Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁹ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁰ Gewebebank des Klinikums rechts der Isar und der Technischen Universität München Am Institut für Pathologie der TU München, München, Germany.
²¹ Department cBITE, MERLN Institute, Maastricht University, Maastricht, The Netherlands.
²² Institute of Molecular Oncology and Functional Genomics, TUM School of Medicine, Technical University of Munich, Munich, Germany.
²³ Department of Medicine II, Klinikum rechts der Isar, TUM School of Medicine, Technical University of Munich, Munich, Germany.
²⁴ Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Greece.
²⁵ 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), Munich, Germany.
²⁶ Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Technical University of Munich, Munich, Germany.
²⁷ The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
²⁸ Department of Medical Biology, The University of Melbourne, Melbourne, Australia.
²⁹ Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁰ Department of Medicine III, Klinikum rechts der Isar, TUM School of Medicine, Technical University of Munich, Munich, Germany. [email protected].
³¹ Center for Translational Cancer Research (TranslaTUM), Technical University of Munich, Munich, Germany. [email protected].
³² German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. [email protected].
³³ Division of Clinical Oncology, Department of Medicine, Medical University of Graz, Graz, Austria. [email protected].

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Antineoplastic Agents / therapeutic use
Apoptosis / drug effects
Apoptosis / genetics
Carcinoma, Non-Small-Cell Lung / diagnostic imaging
Carcinoma, Non-Small-Cell Lung / drug therapy
Carcinoma, Non-Small-Cell Lung / genetics*
Carcinoma, Non-Small-Cell Lung / pathology
Cell Line, Tumor
Cell Survival / drug effects
Cell Survival / genetics
Clonal Evolution
DNA Copy Number Variations
Datasets as Topic
Disease Models, Animal
Disease Progression
Humans
Lung / diagnostic imaging
Lung / pathology
Lung Neoplasms / diagnostic imaging
Lung Neoplasms / drug therapy
Lung Neoplasms / genetics*
Lung Neoplasms / pathology
Mice
Mice, Transgenic
Mutation
Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors
Myeloid Cell Leukemia Sequence 1 Protein / genetics*
Primary Cell Culture
Prospective Studies
Proto-Oncogene Proteins p21(ras) / genetics
Pyrimidines / pharmacology
Pyrimidines / therapeutic use
RNA-Seq
Retrospective Studies
Spheroids, Cellular
Thiophenes / pharmacology
Thiophenes / therapeutic use
Tumor Burden / drug effects
Tumor Burden / genetics
Tumor Suppressor Protein p53 / genetics
X-Ray Microtomography

Substances

Antineoplastic Agents
MCL1 protein, human
Mcl1 protein, mouse
Myeloid Cell Leukemia Sequence 1 Protein
Pyrimidines
S63845
TP53 protein, human
Thiophenes
Trp53 protein, mouse
Tumor Suppressor Protein p53
Hras protein, mouse
Proto-Oncogene Proteins p21(ras)

Abstract

Publication types

MeSH terms

Substances

Grants and funding