FGF19 Is Coamplified With CCND1 to Promote Proliferation in Lung Squamous Cell Carcinoma and Their Combined Inhibition Shows Improved Efficacy.
CCND1
CDK4/6
FGF19
FGFR4
LUSC
amplification
combined inhibition
Journal
Frontiers in oncology
ISSN: 2234-943X
Titre abrégé: Front Oncol
Pays: Switzerland
ID NLM: 101568867
Informations de publication
Date de publication:
2022
2022
Historique:
received:
31
12
2021
accepted:
28
02
2022
entrez:
25
4
2022
pubmed:
26
4
2022
medline:
26
4
2022
Statut:
epublish
Résumé
Lung squamous cell carcinoma (LUSC) remains as a major cause of cancer-associated mortality with few therapeutic options. Continued research on new driver genes is particularly important. FGF19, a fibroblast growth factor, is frequently observed as amplified in human LUSC, which is also associated with multiple genomic gains and losses. However, the importance of these associated changes is largely unknown. In this study, we aimed to clarify a novel mechanism that link neighboring oncogene co-amplification in the development of LUSC. We found that FGF19 was co-amplified and co-expressed with its neighboring gene CCND1 in a subset of LUSC patients and associated with poor prognosis. Moreover, FGF19 combined with CCND1 promoted the cell cycle progression of LUSC cells. Mechanistically, FGF19 also enhanced CCND1 expression by activating FGFR4-ERK1/2 signaling and strengthening CCND1-induced phosphorylation and inactivation of retinoblastoma (RB). In a murine model of lung orthotopic cancer, knockdown of CCND1 was found to prolong survival by attenuating FGF19-induced cell proliferation. Furthermore, the combination treatment of the FGFR4 inhibitor BLU9931 and the CDK4/6 inhibitor palbociclib potentiated the growth inhibition and arrested cells in G1 phase.
Identifiants
pubmed: 35463335
doi: 10.3389/fonc.2022.846744
pmc: PMC9021371
doi:
Types de publication
Journal Article
Langues
eng
Pagination
846744Informations de copyright
Copyright © 2022 Zhang, Wu, Li, Cheng, Han, Lu, Lu and Xia.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer WC declared a shared affiliation with the authors to the handling editor at the time of review.
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