2. Academic Validation
  3. Glucocorticoid receptor triggers a reversible drug-tolerant dormancy state with acquired therapeutic vulnerabilities in lung cancer

Glucocorticoid receptor triggers a reversible drug-tolerant dormancy state with acquired therapeutic vulnerabilities in lung cancer

  • Nat Commun. 2021 Jul 16;12(1):4360. doi: 10.1038/s41467-021-24537-3.
Stefan Prekovic  # 1,  Karianne Schuurman  # 2,  Isabel Mayayo-Peralta 2,  Anna G Manjón 3,  Mark Buijs 2,  Selçuk Yavuz 2,  Max D Wellenstein 4,  Alejandro Barrera 5,  Kim Monkhorst 6,  Anne Huber 2 7,  Ben Morris 8,  Cor Lieftink 8,  Theofilos Chalkiadakis 2,  Ferhat Alkan 2,  Joana Silva 2,  Balázs Győrffy 9 10,  Liesbeth Hoekman 11,  Bram van den Broek 12,  Hans Teunissen 13,  Donna O Debets 14,  Tesa Severson 2,  Jos Jonkers 15,  Timothy Reddy 5,  Karin E de Visser 4,  William Faller 2,  Roderick Beijersbergen 8,  Maarten Altelaar 11 14,  Elzo de Wit 13,  Rene Medema 3,  Wilbert Zwart 16 17
Affiliations

Affiliations

  • 1 Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands. s.prekovic@nki.nl.
  • 2 Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • 3 Division of Cell Biology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • 4 Division of Tumour Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • 5 Department of Biostatistics & Bioinformatics, and Centre for Genomic & Computational Biology, Duke University Medical Centre, Durham, NC, USA.
  • 6 Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • 7 Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Melbourne, VIC, Australia.
  • 8 Division of Molecular Carcinogenesis and Robotics and Screening Centre, Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • 9 Semmelweis University Department of Bioinformatics and 2nd Department of Pediatrics, Budapest, Hungary.
  • 10 TTK Cancer Biomarker Research Group, Institute of Enzymology, Budapest, Hungary.
  • 11 Mass spectrometry/Proteomics Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • 12 Division of Cell Biology and BioImaging Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • 13 Division of Gene Regulation, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • 14 Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
  • 15 Division of Molecular Pathology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • 16 Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands. w.zwart@nki.nl.
  • 17 Laboratory of Chemical Biology and Institute for Complex Molecular Systems, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands. w.zwart@nki.nl.
  • # Contributed equally.
PMID: 34272384 DOI: 10.1038/s41467-021-24537-3
Abstract

The Glucocorticoid Receptor (GR) regulates gene expression, governing aspects of homeostasis, but is also involved in Cancer. Pharmacological GR activation is frequently used to alleviate therapy-related side-effects. While prior studies have shown GR activation might also have anti-proliferative action on tumours, the underpinnings of glucocorticoid action and its direct effectors in non-lymphoid solid cancers remain elusive. Here, we study the mechanisms of glucocorticoid response, focusing on lung Cancer. We show that GR activation induces reversible Cancer cell dormancy characterised by Anticancer drug tolerance, and activation of growth factor survival signalling accompanied by vulnerability to inhibitors. GR-induced dormancy is dependent on a single GR-target gene, CDKN1C, regulated through chromatin looping of a GR-occupied upstream distal enhancer in a SWI/SNF-dependent fashion. These insights illustrate the importance of GR signalling in non-lymphoid solid Cancer biology, particularly in lung Cancer, and warrant caution for use of glucocorticoids in treatment of Anticancer therapy related side-effects.

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