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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Prekovic, S; Schuurman, K; Mayayo-Peralta, I; Manjón, AG; Buijs, M; Yavuz, S; Wellenstein, MD; Barrera, A; Monkhorst, K; Huber, A; Morris, B; Lieftink, C; Chalkiadakis, T; Alkan, F; Silva, J; Győrffy, B; Hoekman, L; van den Broek, B; Teunissen, H; Debets, DO; Severson, T; Jonkers, J; Reddy, T; de Visser, KE; Faller, W; Beijersbergen, R; Altelaar, M; de Wit, E; Medema, R; Zwart, W

Published Date

  • July 16, 2021

Published In

Volume / Issue

  • 12 / 1

Start / End Page

  • 4360 -

PubMed ID

  • 34272384

Pubmed Central ID

  • PMC8285479

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/s41467-021-24537-3

Language

  • eng

Conference Location

  • England