Synapse - A druggable FOXA1-glucocorticoid receptor transcriptional axis drives tumor growth in a subset of non-small cell lung cancer

A druggable FOXA1-glucocorticoid receptor transcriptional axis drives tumor growth in a subset of non-small cell lung cancer Journal Article

Authors:	Dorso, M.; Patel, P. T.; Pankov, A.; Boyer, J. A.; Soni, R. K.; Del Priore, I. S.; Hayatt, O.; Kulick, A.; Hagen, C. J.; de Stanchina, E.; Junttila, M. R.; Daemen, A.; Friedman, L. S.; Hendrickson, R. C.; Chandarlapaty, S.
Article Title:	A druggable FOXA1-glucocorticoid receptor transcriptional axis drives tumor growth in a subset of non-small cell lung cancer
Abstract:	The FOXA1 pioneer factor is an essential mediator of steroid receptor function in multiple hormone-dependent cancers, including breast and prostate cancers, enabling nuclear receptors such as estrogen receptor (ER) and androgen receptor (AR) to activate lineage-specific growth programs. FOXA1 is also highly expressed in non-small cell lung cancer (NSCLC), but whether and how it regulates tumor growth in this context is not known. Analyzing data from loss-of-function screens, we identified a subset of NSCLC tumor lines where proliferation is FOXA1 dependent. Using rapid immunoprecipitation and mass spectrometry of endogenous protein, we identified chromatin-localized interactions between FOXA1 and glucocorticoid receptor (GR) in these tumor cells. Knockdown of GR inhibited proliferation of FOXA1-dependent, but not FOXA1-independent NSCLC cells. In these FOXA1-dependent models, FOXA1 and GR cooperate to regulate gene targets involved in EGF signaling and G1-S cell-cycle progression. To investigate the therapeutic potential for targeting this complex, we examined the effects of highly selective inhibitors of the GR ligand-binding pocket and found that GR antagonism with ORIC-101 suppressed FOXA1/GR target expression, activation of EGF signaling, entry into the S-phase, and attendant proliferation in vitro and in vivo. Taken together, our findings point to a subset of NSCLCs harboring a dependence on the FOXA1/GR growth program and provide rationale for its therapeutic targeting.Significance: NSCLC is the leading cause of cancer deaths worldwide. There is a need to identify novel druggable dependencies. We identify a subset of NSCLCs dependent on FOXA1-GR and sensitive to GR antagonism.
Keywords:	gene; estrogen; progression; androgen receptor; breast-cancer; expression; reveals; mass-spectrometry; glucocorticoid-receptor; foxa1
Journal Title:	Cancer Research Communications
Volume:	3
Issue:	9
ISSN:	2767-9764
Publisher:	American Association for Cancer Research
Date Published:	2023-09-01
Start Page:	1788
End Page:	1799
Language:	English
ACCESSION:	WOS:001104408800012
DOI:	10.1158/2767-9764.Crc-23-0310
PROVIDER:	wos
PMCID:	PMC10484118
PUBMED:	37691854
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding author is MSK author: Sarat Chandarlapaty -- Source: Wos