FGFR1 and FGFR4 oncogenicity depends on n-cadherin and their co-expression may predict FGFR-targeted therapy efficacy Journal Article
| Authors: | Quintanal-Villalonga, Á; Ferrer, I.; Guruceaga, E.; Cirauqui, C.; Marrugal, Á; Ojeda, L.; García, S.; Zugazagoitia, J.; Muñoz-Galván, S.; Lopez-Rios, F.; Montuenga, L.; Vicent, S.; Molina-Pinelo, S.; Carnero, A.; Paz-Ares, L. |
| Article Title: | FGFR1 and FGFR4 oncogenicity depends on n-cadherin and their co-expression may predict FGFR-targeted therapy efficacy |
| Abstract: | 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: 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: 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: 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. © 2020 The Authors |
| Keywords: | immunohistochemistry; signal transduction; controlled study; human tissue; protein expression; human cell; major clinical study; overall survival; nonhuman; animal tissue; gene overexpression; stat3 protein; reverse transcription polymerase chain reaction; confocal microscopy; tumor volume; animal experiment; animal model; cohort analysis; lung cancer; immunofluorescence; lung tumor; genetic transfection; nerve cell adhesion molecule; western blotting; carcinogenicity; immunoprecipitation; immunoblotting; down regulation; upregulation; gene silencing; tumor growth; clonogenic assay; transcriptome; fibroblast growth factor receptor 1; rna extraction; non small cell lung cancer; colony formation; fibroblast growth factor receptor 4; transcription factor mash1; growth curve; fgfr4; predictive biomarker; dovitinib; azd 4547; n-cadherin; human; female; priority journal; article; fgfr1; infigratinib; neurogenic differentiation factor; mrna expression level; fgfr inhibitors; transcription factor pou |
| Journal Title: | EBioMedicine |
| Volume: | 53 |
| ISSN: | 2352-3964 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2020-03-01 |
| Start Page: | 102683 |
| Language: | English |
| DOI: | 10.1016/j.ebiom.2020.102683 |
| PROVIDER: | scopus |
| PMCID: | PMC7047190 |
| PUBMED: | 32114392 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 April 2020 -- Source: Scopus |
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