FGFR1 and FGFR4 oncogenicity depends on n-cadherin and their co-expression may predict FGFR-targeted therapy efficacy.
Animals
Antineoplastic Agents
/ therapeutic use
Benzamides
/ therapeutic use
Biomarkers, Tumor
/ genetics
Cadherins
/ genetics
Carcinoma, Non-Small-Cell Lung
/ drug therapy
Cell Line, Tumor
Drug Resistance, Neoplasm
Female
Humans
Lung Neoplasms
/ drug therapy
Mice
Mice, Nude
Piperazines
/ therapeutic use
Pyrazoles
/ therapeutic use
Receptor, Fibroblast Growth Factor, Type 1
/ antagonists & inhibitors
Receptor, Fibroblast Growth Factor, Type 4
/ antagonists & inhibitors
Tumor Cells, Cultured
FGFR inhibitors
FGFR1
FGFR4
N-cadherin
Predictive biomarker
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Mar 2020
Mar 2020
Historique:
received:
09
10
2019
revised:
05
02
2020
accepted:
05
02
2020
pubmed:
3
3
2020
medline:
18
12
2020
entrez:
2
3
2020
Statut:
ppublish
Résumé
Fibroblast growth factor receptor (FGFR)1 and FGFR4 have been associated with tumorigenesis in a variety of tumour types. As a therapeutic approach, their inhibition has been attempted in different types of malignancies, including lung cancer, and was initially focused on FGFR1-amplified tumours, though with limited success. In vitro and in vivo functional assessments of the oncogenic potential of downregulated/overexpressed genes in isogenic cell lines were performed, as well as inhibitor efficacy tests in vitro and in vivo in patient-derived xenografts (PDXs). mRNA was extracted from FFPE non-small cell lung cancer samples to determine the prognostic potential of the genes under study. We provide in vitro and in vivo evidence showing that expression of the adhesion molecule N-cadherin is key for the oncogenic role of FGFR1/4 in non-small cell lung cancer. According to this, assessment of the expression of genes in different lung cancer patient cohorts showed that FGFR1 or FGFR4 expression alone showed no prognostic potential, and that only co-expression of FGFR1 and/or FGFR4 with N-cadherin inferred a poorer outcome. Treatment of high-FGFR1 and/or FGFR4-expressing lung cancer cell lines and patient-derived xenografts with selective FGFR inhibitors showed high efficacy, but only in models with high FGFR1/4 and N-cadherin expression. Our data show that the determination of the expression of FGFR1 or FGFR4 alone is not sufficient to predict anti-FGFR therapy efficacy; complementary determination of N-cadherin expression may further optimise patient selection for this therapeutic strategy.
Sections du résumé
BACKGROUND
BACKGROUND
Fibroblast growth factor receptor (FGFR)1 and FGFR4 have been associated with tumorigenesis in a variety of tumour types. As a therapeutic approach, their inhibition has been attempted in different types of malignancies, including lung cancer, and was initially focused on FGFR1-amplified tumours, though with limited success.
METHODS
METHODS
In vitro and in vivo functional assessments of the oncogenic potential of downregulated/overexpressed genes in isogenic cell lines were performed, as well as inhibitor efficacy tests in vitro and in vivo in patient-derived xenografts (PDXs). mRNA was extracted from FFPE non-small cell lung cancer samples to determine the prognostic potential of the genes under study.
FINDINGS
RESULTS
We provide in vitro and in vivo evidence showing that expression of the adhesion molecule N-cadherin is key for the oncogenic role of FGFR1/4 in non-small cell lung cancer. According to this, assessment of the expression of genes in different lung cancer patient cohorts showed that FGFR1 or FGFR4 expression alone showed no prognostic potential, and that only co-expression of FGFR1 and/or FGFR4 with N-cadherin inferred a poorer outcome. Treatment of high-FGFR1 and/or FGFR4-expressing lung cancer cell lines and patient-derived xenografts with selective FGFR inhibitors showed high efficacy, but only in models with high FGFR1/4 and N-cadherin expression.
INTERPRETATION
CONCLUSIONS
Our data show that the determination of the expression of FGFR1 or FGFR4 alone is not sufficient to predict anti-FGFR therapy efficacy; complementary determination of N-cadherin expression may further optimise patient selection for this therapeutic strategy.
Identifiants
pubmed: 32114392
pii: S2352-3964(20)30058-X
doi: 10.1016/j.ebiom.2020.102683
pmc: PMC7047190
pii:
doi:
Substances chimiques
AZD4547
0
Antineoplastic Agents
0
Benzamides
0
Biomarkers, Tumor
0
Cadherins
0
Piperazines
0
Pyrazoles
0
FGFR1 protein, human
EC 2.7.10.1
FGFR4 protein, human
EC 2.7.10.1
Receptor, Fibroblast Growth Factor, Type 1
EC 2.7.10.1
Receptor, Fibroblast Growth Factor, Type 4
EC 2.7.10.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
102683Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest Drs Quintanal-Villalonga, Molina-Pinelo, Carnero, Paz-Ares, and Ferrer jointly hold patent WO2019012174A1 and patent WO2019016422A1 (pending). Dr. Paz-Ares also reports personal fees from Roche, Lilly, MSD, BMS, AstraZeneca, Boehringer Ingelheim, Pfizer, Takeda, Novartis, Merck Serono, Amgen, Sanofi, Pharmamar, Clovis Oncology and Janssen outside the submitted work. JZ reports personal fees from Guardant Health. The remaining authors declare no conflict of interest.
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