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

Stefan Prekovic (), Karianne Schuurman, Isabel Mayayo-Peralta, Anna G. Manjón, Mark Buijs, Selçuk Yavuz, Max D. Wellenstein, Alejandro Barrera, Kim Monkhorst, Anne Huber, Ben Morris, Cor Lieftink, Theofilos Chalkiadakis, Ferhat Alkan, Joana Silva, Balázs Győrffy, Liesbeth Hoekman, Bram Broek, Hans Teunissen, Donna O. Debets, Tesa Severson, Jos Jonkers, Timothy Reddy, Karin E. Visser, William Faller, Roderick Beijersbergen, Maarten Altelaar, Elzo Wit, Rene Medema and Wilbert Zwart ()
Additional contact information
Stefan Prekovic: The Netherlands Cancer Institute
Karianne Schuurman: The Netherlands Cancer Institute
Isabel Mayayo-Peralta: The Netherlands Cancer Institute
Anna G. Manjón: The Netherlands Cancer Institute
Mark Buijs: The Netherlands Cancer Institute
Selçuk Yavuz: The Netherlands Cancer Institute
Max D. Wellenstein: Oncode Institute, The Netherlands Cancer Institute
Alejandro Barrera: Duke University Medical Centre
Kim Monkhorst: The Netherlands Cancer Institute
Anne Huber: The Netherlands Cancer Institute
Ben Morris: Netherlands Cancer Institute
Cor Lieftink: Netherlands Cancer Institute
Theofilos Chalkiadakis: The Netherlands Cancer Institute
Ferhat Alkan: The Netherlands Cancer Institute
Joana Silva: The Netherlands Cancer Institute
Balázs Győrffy: Semmelweis University Department of Bioinformatics and 2nd Department of Pediatrics
Liesbeth Hoekman: The Netherlands Cancer Institute
Bram Broek: The Netherlands Cancer Institute
Hans Teunissen: The Netherlands Cancer Institute
Donna O. Debets: Utrecht University
Tesa Severson: The Netherlands Cancer Institute
Jos Jonkers: Oncode Institute, The Netherlands Cancer Institute
Timothy Reddy: Duke University Medical Centre
Karin E. Visser: Oncode Institute, The Netherlands Cancer Institute
William Faller: The Netherlands Cancer Institute
Roderick Beijersbergen: Netherlands Cancer Institute
Maarten Altelaar: The Netherlands Cancer Institute
Elzo Wit: The Netherlands Cancer Institute
Rene Medema: The Netherlands Cancer Institute
Wilbert Zwart: The Netherlands Cancer Institute

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24537-3

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