FGFR1 and FGFR4 oncogenicity depends on n-cadherin and their coexpression may predict FGFR-targeted therapy efficacy
| Autor: | Santiago García, Luis Paz-Ares, Fernando Lopez-Rios, Jon Zugazagoitia, Sonia Molina-Pinelo, Laura Ojeda, Irene Ferrer, Sandra Muñoz-Galván, Elizabeth Guruceaga, Luis M. Montuenga, Silvestre Vicent, Cristina Cirauqui, Álvaro Quintanal-Villalonga, Amancio Carnero, Ángela Marrugal |
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| Přispěvatelé: | [Quintanal-Villalonga,Á, Ferrer,I, Cirauqui,C, Marrugal,Á, Ojeda,L, García,S, Zugazagoitia,J, Paz-Ares,L] H12O-CNIO Lung Cancer Clinical Research Unit, Instituto de Investigacion Hospital 12 de Octubre & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain. [Quintanal-Villalonga,Á] Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. [Ferrer,I, Muñoz-Galván,S, Lopez-Rios,F, Montuenga,L, Vicent,S, Molina-Pinelo,S, Carnero,A, Paz-Ares,L] CIBERONC, Madrid, Spain. [Guruceaga,E] Bioinformatics Unit, Centre for Applied Medical Research (CIMA), Pamplona, Spain. [Guruceaga,E] PROTEORED, Madrid, Spain. [Zugazagoitia,J, Paz-Ares,L] Medical Oncology Department, Hospital Universitario Doce de Octubre. Madrid, Spain. [Muñoz-Galván,S, Carnero,A] Instituto de Biomedicina de Sevilla (IBIS) (HUVR, CSIC, Universidad de Sevilla), Sevilla, Spain. [Lopez-Rios,F] Laboratorio de Dianas Terapeuticas, Hospital Universitario HM Sanchinarro, Madrid, Spain. [Montuenga,L, Vicent,S] Program in Solid Tumors, Centre for Applied Medical Research (CIMA), Pamplona, Spain. [Montuenga,L, Vicent,S] Department of Pathology, Anatomy and Physiology, University of Navarra, Pamplona, Spain. [Montuenga,L, Vicent,S] IdiSNA, Navarra Institute for Health Research, Pamplona, SPAIN. [Paz-Ares,L] Medical School, Universidad Complutense, Madrid, Spain., This work was funded by the Community of Madrid, the ISCIII cofunded by FEDER from Regional Development European Funds (European Union), the Spanish Ministry of Economy and Competitiveness, the Mutua Madrilena Foundation, the Ministry of Health and Social ~ Welfare of Junta de Andalucía, the AECC scientific foundation and the Spanish Ministry of Education, Culture and Sport. L.P.A. was funded by the Community of Madrid, CAM, (B2017/BMD3884), ISCIII (PIE15/00076, PI17/00778 and DTS17/00089) and CIBERONC (CD16/12/00442), and co-funded by FEDER from Regional Development European Funds (European Union). A.C. was funded by grants from the Spanish Ministry of Economy and Competitiveness Plan Estatal de I+D+I 2018 cofunded by FEDER: RTI2018-097455-B-I00, CIBER de Cancer (CB16/ 12/00275), co-funded by FEDER from Regional Development European Funds. S.M.P. is funded by the Mutua Madrilena Foundation ~ (2014) Ministry of Health and Social Welfare of Junta de Andalucía (PI-0046-2012, Nicolas Monardes Program C-0040-2016), ISCIII (PI17/00033), and co-funded by FEDER from Regional Development European Funds (European Union). I.F. is funded by the AECC scientific foundation (AIO2015) and Consejería de Igualdad, Salud y Políticas Sociales de la Junta de Andalucía (PI-0029-2013) and ISCIII (PI16/ 01311) and co-funded by FEDER from Regional Development European Funds (European Union). A.Q. is funded by ISCIII (FI12/00429). L. O. is funded by the Spanish Ministry of Education, Culture and Sport (FPU13/02595). S.V. is supported by the Spanish Ministry of Economy and Competitiveness (MINECO, SAF2017-89944-R)., Comunidad de Madrid, Instituto de Salud Carlos III, European Commission, Ministerio de Economía y Competitividad (España), Fundación Mutua Madrileña, Junta de Andalucía, Fundación Científica Asociación Española Contra el Cáncer, Ministerio de Educación, Cultura y Deporte (España), European Regional Development Fund, Regional Government of Andalusia (España), Asociación Española Contra el Cáncer, European Regional Development Fund (ERDF/FEDER), Fundación Mutua Madrileña Automovilista, Gobierno de Andalucia, Asociacion Espanola Contra el Cancer (AECC) |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Anatomy::Cells::Cells Cultured::Cell Line::Cell Line Tumor [Medical Subject Headings] Lung Neoplasms Research paper medicine.medical_treatment lcsh:Medicine medicine.disease_cause Piperazines Targeted therapy Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings] Mice 0302 clinical medicine Lung neoplasms Carcinoma Non-Small-Cell Lung Phenomena and Processes::Physiological Phenomena::Pharmacological Phenomena::Drug Resistance::Drug Resistance Neoplasm [Medical Subject Headings] Tumor Cells Cultured Organisms::Eukaryota::Animals [Medical Subject Headings] FGFR inhibitors Receptor tipo 1 de factor de crecimiento de fibroblastos Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Protein Kinases::Protein-Tyrosine Kinases::Receptor Protein-Tyrosine Kinases::Receptor Fibroblast Growth Factor Type 1 [Medical Subject Headings] lcsh:R5-920 Diseases::Neoplasms::Neoplasms by Site::Thoracic Neoplasms::Respiratory Tract Neoplasms::Lung Neoplasms::Bronchial Neoplasms::Carcinoma Bronchogenic::Carcinoma Non-Small-Cell Lung [Medical Subject Headings] Receptor tipo 4 de factor de crecimiento de fibroblastos Anatomy::Cells::Cells Cultured::Tumor Cells Cultured [Medical Subject Headings] General Medicine Cadherins Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Protein Kinases::Protein-Tyrosine Kinases::Receptor Protein-Tyrosine Kinases::Receptor Fibroblast Growth Factor Type 4 [Medical Subject Headings] Predictive biomarker Fibroblast growth factor receptor 030220 oncology & carcinogenesis Benzamides Female lcsh:Medicine (General) Neoplasias pulmonares Mice Nude Antineoplastic Agents Diseases::Neoplasms::Neoplasms by Site::Thoracic Neoplasms::Respiratory Tract Neoplasms::Lung Neoplasms [Medical Subject Headings] General Biochemistry Genetics and Molecular Biology 03 medical and health sciences In vivo Cell Line Tumor Biomarkers Tumor medicine Chemicals and Drugs::Biological Factors::Biological Markers [Medical Subject Headings] Animals Humans Receptor Fibroblast Growth Factor Type 4 Receptor Fibroblast Growth Factor Type 1 Lung cancer N-cadherin Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings] business.industry Fibroblast growth factor receptor 1 lcsh:R Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents [Medical Subject Headings] Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice::Mice Mutant Strains::Mice Nude [Medical Subject Headings] Fibroblast growth factor receptor 4 Chemicals and Drugs::Amino Acids Peptides and Proteins::Proteins::Glycoproteins::Membrane Glycoproteins::Cell Adhesion Molecules::Cadherins [Medical Subject Headings] medicine.disease Isogenic human disease models stomatognathic diseases 030104 developmental biology Biomarcadores FGFR1 Check Tags::Female [Medical Subject Headings] Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds 1-Ring::Azoles::Pyrazoles [Medical Subject Headings] Drug Resistance Neoplasm Cancer research FGFR4 Pyrazoles Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds 1-Ring::Piperazines [Medical Subject Headings] Carcinogenesis business Chemicals and Drugs::Organic Chemicals::Amides::Benzamides [Medical Subject Headings] Biomarkers Cadherinas |
| Zdroj: | EBioMedicine EBioMedicine, Vol 53, Iss, Pp-(2020) Digital.CSIC. Repositorio Institucional del CSIC instname Repisalud Instituto de Salud Carlos III (ISCIII) |
| Popis: | [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. This work was funded by the Community of Madrid, the ISCIII co-funded by FEDER from Regional Development European Funds (European Union), the Spanish Ministry of Economy and Competitiveness, the Mutua Madrileña Foundation, the Ministry of Health and Social Welfare of Junta de Andalucía, the AECC scientific foundation and the Spanish Ministry of Education, Culture and Sport. |
| Databáze: | OpenAIRE |
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