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 patientderived 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.

The FGFR4-388Arg variant has been related to poor prognosis in several types of cancer, including lung cancer. The mechanism underlying this association has not been addressed in detail in patients with this pathology. Here, we report that this FGFR4 variant induces MAPK and STAT3 activation and causes pro-oncogenic effects in NSCLC in vitro and in vivo. This variant induces the expression of EMT-related genes, such as N-cadherin, vimentin, Snail1 and Twist1. Indeed, the induction of N-cadherin protein expression by this variant is essential for its pro-tumorigenic role. The presence of the FGFR4-388Arg variant correlates with higher N-cadherin expression levels in clinical NSCLC samples and with poorer outcome in patients with FGFR expression. These results support the prognostic role of this FGFR variant in lung cancer and show that these effects may be mediated by the induction of N-cadherin expression and an EMT phenotype.

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FGFR family of proteins has been extensively related to oncogenic properties in several types of tumors, including lung cancer. Among its members, FGFR1 has been related to squamous cell lung carcinoma, where FGFR1 amplification is present in 20% of patients. However, its role in lung cancer has not yet been thoroughly described. Several lung cancer cell lines with different genetic backgrounds were transfected with plasmids to either overexpress or silence FGFR1. Then several tumorigenic abilities were tested in vitro and in vivo. mRNA from Paraffin-embedded tissue of a cohort of lung cancer patients was extracted and FGFR1 expression levels were measured and related to clinical characteristics. FGFR1 increases oncogenic properties in SCC cell lines, but exerts anti-oncogenic effects in several lung ADC cell lines, suggesting a tumor suppressor role under certain circumstances. This is a consequence of differentially expressed genes among these two histologies. According to this, analysis of FGFR1 mRNA expression of a cohort of lung cancer patients revealed that high FGFR1 mRNA expression was associated to a shorter overall survival (OS) and progression free survival (PFS) in lung SCC patients. However, a trend for longer OS was observed for the ADC patients with higher FGFR1 mRNA expression. FGFR1 has the potential to be either a tumor suppressor or an oncogene and the molecular context is a determining factor to define its final role in tumorigenesis. Citation Format: Álvaro Quintanal-Villalonga, Laura Ojeda-Márquez, Ángela Marrugal, Rocío Suárez, Irene Ferrer, Amancio Carnero, Sonia Molina-Pinelo, Luis Paz-Ares. FGFR1 can act as an oncogene or a tumor suppressor depending on the molecular context. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1122.

were used. Pharmacological inhibition of HSP90 activity in these cell lines were achieved through geldanamycin and resorcinol derivatives. The response to these inhibitors at different time points was evaluated. Results: Westerns blots indicated that HSP70 and HSP90-a protein expression were increased after 17-AAG, IPI-504, STA-9090 and AUY-922 treatments. EGFR, EML4-ALK and CDK4, the oncogenic client proteins studied, were depleted by the HSP90 inhibitors in the NSCLC cell lines. The strong relationship between client driver protein dependence on Hsp90 and the sensitivity to its inhibition was demonstrated in the HCC827 and H3122 cell lines. Conclusions: The reduction of oncogenic client proteins alongside HSP70 and HSP90-a induction could be used as a validated biomarker signature of HSP90 inhibition in the cell lines studied. Future study will be focused on understanding the biological basis for the differential response to these treatments. Legal entity responsible for the study:

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The FGFR4-388Arg allele, where an arginine substitutes a glycine in the 388 codon of the FGFR4 gene, has been associated to poorer patient outcome in different tumor types. In lung cancer, the variant has been related to shorter overall survival in adenocarcinoma (ADC) patients, while no relationship with squamous cell carcinoma prognosis (SCC) has been reported. Mechanistically, the FGFR4-388Arg variant has been related to increased MAPK pathway activation and to EMT in prostate cancer in vitro models. Furthermore, the variant has been associated with higher STAT3 signaling in murine models of breast and lung cancer. However, so far the molecular biology for this FGFR4 variant in lung cancer patients has not been addressed. We overexpressed the FGFR4-388Gly and FGFR4-388Arg variants in lung cancer cell lines from different histologic backgrounds and performed tumorogenicity surrogate assays and downstream signaling activation assessment. In the generated stable cell lines, we also determined the expression of EMT markers. Furthermore, we determined the FGFR4 variant and the FGFR4 and N-cadherin mRNA expression in a cohort of NSCLC patients (N=65) and correlated these data to patient outcome. We reported that FGFR4-388Arg increases tumorogenicity in lung cancer cell lines. Mechanistically, these functional effects seem to be mediated by MAPK and STAT3 overactivation and by the induction of an EMT phenotype, which includes N-cadherin increased expression. In fact, this induction of N-cadherin protein expression by the FGFR4-388Arg variant seems to be responsible for the pro-oncogenic effects reported. In NSCLC patient tumor samples, the FGFR4-388Arg variant correlates with higher N-cadherin expression and with poorer survival. In conclusion, the FGFR4-388Arg variant is a potential prognostic biomarker in NSCLC, including ADC and SCC patients. This variant increases tumorogenesis through the activation of MAPK and STAT3 signaling pathways and through the promotion of an EMT phenotype. Citation Format: Álvaro Quintanal-Villalonga, Rocío Suárez, Laura Ojeda-Márquez, Santiago Ponce-Aix, Amancio Carnero, Luis Paz-Ares, Irene Ferrer, Sonia Molina-Pinelo. The FGFR4-388Arg variant exerts pro-tumorogenic effects in lung cancer by inducing an EMT phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3334. doi:10.1158/1538-7445.AM2017-3334