TY - JOUR
T1 - FGFR1 Cooperates with EGFR in Lung Cancer Oncogenesis, and Their Combined Inhibition Shows Improved Efficacy
AU - Quintanal-Villalonga, Alvaro
AU - Molina-Pinelo, Sonia
AU - Cirauqui, Cristina
AU - Ojeda-Márquez, Laura
AU - Marrugal, Ángela
AU - Suarez, Rocío
AU - Conde, Esther
AU - Ponce-Aix, Santiago
AU - Enguita, Ana Belén
AU - Carnero, Amancio
AU - Ferrer, Irene
AU - Paz-Ares, Luis
N1 - Publisher Copyright:
© 2019 International Association for the Study of Lung Cancer
PY - 2019/4/1
Y1 - 2019/4/1
N2 - Introduction: There 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. Methods: We 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. Results: We 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. Conclusion: These 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.
AB - Introduction: There 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. Methods: We 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. Results: We 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. Conclusion: These 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.
KW - EGFR
KW - FGFR1
KW - combined inhibition
KW - cooperation
UR - http://www.scopus.com/inward/record.url?scp=85063268079&partnerID=8YFLogxK
U2 - 10.1016/j.jtho.2018.12.021
DO - 10.1016/j.jtho.2018.12.021
M3 - Article
C2 - 30639621
AN - SCOPUS:85063268079
SN - 1556-0864
VL - 14
SP - 641
EP - 655
JO - Journal of Thoracic Oncology
JF - Journal of Thoracic Oncology
IS - 4
ER -