FGFR1 Cooperates with EGFR in Lung Cancer Oncogenesis,and Their Combined Inhibition Shows Improved Efficacy |
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Authors: | Alvaro Quintanal-Villalonga Sonia Molina-Pinelo Cristina Cirauqui Laura Ojeda-Márquez Ángela Marrugal Rocío Suarez Esther Conde Santiago Ponce-Aix Ana Belén Enguita Amancio Carnero Irene Ferrer Luis Paz-Ares |
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Affiliation: | 1. H12O-CNIO Lung Cancer Clinical Research Unit, Biomedical Research Foundation i+12, Madrid, Spain;2. H12O-CNIO Lung Cancer Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain;3. Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York;4. Insitute for Biomedical Research in Seville (UHVR, SNRC, Seville University), Seville, Spain;5. CIBERONC, Madrid, Spain;6. Therapeutic Targets Laboratory, University Hospital HM Sanchinarro, Madrid, Spain;7. Medical Oncology Department, University Hospital Doce de Octubre Madrid, Spain;8. Pathological Anatomy Department, University Hospital Doce de Octubre, Madrid, Spain;9. Medical School, Complutense University, Madrid, Spain |
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Abstract: | IntroductionThere is substantial evidence for the oncogenic effects of fibroblast growth factor receptor 1 (FGFR1) in many types of cancer, including lung cancer, but the role of this receptor has not been addressed specifically in lung adenocarcinoma.MethodsWe performed FGFR1 and EGFR overexpression and co-overexpression assays in adenocarcinoma and in inmortalized lung cell lines, and we also carried out surrogate and interaction assays. We performed monotherapy and combination EGFR/FGFR inhibitor sensitivity assays in vitro and in vivo in cell line– and patient-derived xenografts. We determined FGFR1 mRNA expression in a cohort of patients with anti–EGFR therapy–treated adenocarcinoma.ResultsWe have reported a cooperative interaction between FGFR1 and EGFR in this context, resulting in increased EGFR activation and oncogenic signaling. We have provided in vitro and in vivo evidence indicating that FGFR1 expression increases tumorigenicity in cells with high EGFR activation in EGFR-mutated and EGFR wild-type models. At the clinical level, we have shown that high FGFR1 expression levels predict higher resistance to erlotinib or gefitinib in a cohort of patients with tyrosine kinase inhibitor–treated EGFR-mutated and EGFR wild-type lung adenocarcinoma. Dual EGFR and FGFR inhibition in FGFR1-overexpressing, EGFR-activated models shows synergistic effects on tumor growth in vitro and in cell line– and patient-derived xenografts, suggesting that patients with tumors bearing these characteristics may benefit from combined EGFR/FGFR inhibition.ConclusionThese results support the extended the use of EGFR inhibitors beyond monotherapy in the EGFR-mutated adenocarcinoma setting in combination with FGFR inhibitors for selected patients with increased FGFR1 overexpression and EGFR activation. |
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Keywords: | FGFR1 EGFR cooperation combined inhibition |
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