Fibroblast growth receptor 1 is regulated by G-quadruplex in metastatic breast cancer.

Autor: Lin H; Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA., Hassan Safdar M; Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA., Washburn S; Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA., S Akhand S; Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA., Dickerhoff J; Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA., Ayers M; Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA., Monteiro M; Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA.; Department of Internal Medicine, University of Iowa, Iowa City, IA, USA., Solorio L; Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN, USA.; Department of Biomedical Engineering, Purdue University, West Lafayette, IN, USA., Yang D; Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA. yangdz@purdue.edu.; Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN, USA. yangdz@purdue.edu.; Department of Chemistry, Purdue University, West Lafayette, IN, USA. yangdz@purdue.edu., Wendt MK; Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA. mkwendt@uiowa.edu.; Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN, USA. mkwendt@uiowa.edu.; Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA. mkwendt@uiowa.edu.; Department of Internal Medicine, University of Iowa, Iowa City, IA, USA. mkwendt@uiowa.edu.
Jazyk: angličtina
Zdroj: Communications biology [Commun Biol] 2024 Aug 09; Vol. 7 (1), pp. 963. Date of Electronic Publication: 2024 Aug 09.
DOI: 10.1038/s42003-024-06602-x
Abstrakt: Limiting cellular plasticity is of key importance for the therapeutic targeting of metastatic breast cancer (MBC). Fibroblast growth receptor (FGFR) is a critical molecule in cellular plasticity and potent inhibitors of FGFR enzymatic activity have been developed, but kinase independent functions for this receptor also contribute to MBC progression. Herein, we evaluated several FGFR inhibitors and find that while FGFR-targeted kinase inhibitors are effective at blocking ligand-induced cell growth, dormant cells persist eventually giving rise to MBC progression. To more broadly target FGFR and cellular plasticity, we examined the FGFR1 proximal promoter, and found several sequences with potential to form G-quadruplex secondary structures. Circular dichroism was used to verify formation of G-quadruplex in the FGFR1 proximal promoter. Importantly, use of the clinical G-quadruplex-stabilizing compound, CX-5461, stabilized the FGFR1 G-quadruplex structures, blocked the transcriptional activity of the FGFR1 proximal promoter, decreased FGFR1 expression, and resulted in potent inhibition of pulmonary tumor formation. Overall, our findings suggest G-quadruplex-targeted compounds could be a potential therapeutic strategy to limit the cellular plasticity of FGFR1 overexpressing MBC.
(© 2024. The Author(s).)
Databáze: MEDLINE
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