Abstract Fibroblast growth factor receptor (FGFR)1 has been associated with tumorigenesis in a variety of tumors, including lung cancer. FGFR1 amplification is detected in up to 20% of lung squamous cell carcinomas, and was initially related to tumorigenesis and to response to FGFR inhibitors in preclinical models of this pathology. These data encouraged the establishment of FGFR1 amplification as the main eligibility criterion for inclusion of patients in FGFR inhibitors clinical trials. However, the use of FGFR inhibitors in FGFR1-amplified tumors has shown limited success, with only 5-10% of selected patients showing partial response, suggesting that this genomic aberration may not be a good predictive biomarker for the efficacy of these inhibitors. In this work, we provide in vitro and in vivo data showing that the oncogenic effects of FGFR1 expression depend on the expression of the adhesion molecule N-cadherin in non-small cell lung cancer (NSCLC). In line with these results, FGFR1 expression correlates with poorer prognosis only in tumors with high N-cadherin levels in two independent NSCLC patient cohorts. We observed that high FGFR1 expression alone is not sufficient to predict FGFR inhibition efficacy in lung cancer cell lines and patient-derived xenografts, with only high FGFR1- and high N-cadherin-expressing models responding to selective FGFR inhibitors. Altogether, our data show that the determination of the expression of FGFR1 alone is not sufficient to predict FGFR inhibition efficacy. The co-determination of N-cadherin expression may optimize patient selection for this therapeutic strategy. Citation Format: Álvaro Quintanal-Villalonga, Irene Ferrer, Ángela Marrugal, Laura Ojeda-Márquez, Jon Zugazagoita, Laura García-Redondo, Fernando López-Ríos, Luis Montuenga, Sonia Molina-Pinelo, Sonia Molina-Pinelo, Amancio Carnero, Luis Paz-Ares. Novel predictor of FGFR1 inhibition efficacy in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2589.