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The use of 90 kDa heat shock protein (HSP90) inhibition as a therapy in lung adenocarcinoma remains limited due to moderate drug efficacy, the emergence of drug resistance, and early tumor recurrence. The main objective of this research is to maximize treatment efficacy in lung adenocarcinoma by identifying key proteins underlying HSP90 inhibition according to molecular background, and to search for potential biomarkers of response to this therapeutic strategy. Inhibition of the HSP90 chaperone was evaluated in different lung adenocarcinoma cell lines representing the most relevant molecular alterations (EGFR mutations, KRAS mutations, or EML4-ALK translocation) and wild-type genes found in each tumor subtype. The proteomic technique iTRAQ was used to identify proteomic profiles and determine which biological pathways are involved in the response to HSP90 inhibition in lung adenocarcinoma. We corroborated the greater efficacy of HSP90 inhibition in EGFR mutated or EML4-ALK translocated cell lines. We identified proteins specifically and significantly deregulated after HSP90 inhibition for each molecular alteration. Two proteins, ADI1 and RRP1, showed independently deregulated molecular patterns. Functional annotation of the altered proteins suggested that apoptosis was the only pathway affected by HSP90 inhibition across all molecular subgroups. The expression of ADI1 and RRP1 could be used to monitor the correct inhibition of HSP90 in lung adenocarcinoma. In addition, proteins such as ASS1, ITCH, or UBE2L3 involved in pathways related to the inhibition of a particular molecular background could be used as potential response biomarkers, thereby improving the efficacy of this therapeutic approach to combat lung adenocarcinoma., Depto. de Medicina, Fac. de Medicina, TRUE, pub, Descuento UCM

The use of 90 kDa heat shock protein (HSP90) inhibition as a therapy in lung adenocarcinoma remains limited due to moderate drug efficacy, the emergence of drug resistance, and early tumor recurrence. The main objective of this research is to maximize treatment efficacy in lung adenocarcinoma by identifying key proteins underlying HSP90 inhibition according to molecular background, and to search for potential biomarkers of response to this therapeutic strategy. Inhibition of the HSP90 chaperone was evaluated in different lung adenocarcinoma cell lines representing the most relevant molecular alterations (EGFR mutations, KRAS mutations, or EML4-ALK translocation) and wild-type genes found in each tumor subtype. The proteomic technique iTRAQ was used to identify proteomic profiles and determine which biological pathways are involved in the response to HSP90 inhibition in lung adenocarcinoma. We corroborated the greater efficacy of HSP90 inhibition in EGFR mutated or EML4-ALK translocated cell lines. We identified proteins specifically and significantly deregulated after HSP90 inhibition for each molecular alteration. Two proteins, ADI1 and RRP1, showed independently deregulated molecular patterns. Functional annotation of the altered proteins suggested that apoptosis was the only pathway affected by HSP90 inhibition across all molecular subgroups. The expression of ADI1 and RRP1 could be used to monitor the correct inhibition of HSP90 in lung adenocarcinoma. In addition, proteins such as ASS1, ITCH, or UBE2L3 involved in pathways related to the inhibition of a particular molecular background could be used as potential response biomarkers, thereby improving the efficacy of this therapeutic approach to combat lung adenocarcinoma.

The present invention describes a method for predicting the response of a subject suffering from lung cancer to treatment with FGFR inhibitors. The relationship between the expression of the biomarkers and the treatment response allows the subjects to be classified as responsive or unresponsive to the treatment, which facilitates the therapeutic decision-making of the attending clinician. The present invention also describes the biomarkers N-cadherin, FGFR1 and FGFR4, how to analyse them and how to interpret the results obtained, in order to administer FGFR inhibitors only to the subjects that are responsive to the treatment, thereby optimising the same, which allows the unresponsive subjects to be treated with alternative therapies to the FGFR inhibitors

[Simple Summary] The search for prognostic and/or predictive gene signatures of the response to radiotherapy treatment can significantly aid clinical decision making. These signatures can condition the fractionation, the total dose to be administered, and/or the combination of systemic treatments and radiation. The ultimate goal is to achieve better clinical results, as well as to minimize the adverse effects associated with current cancer therapies. To this end, we analyzed the intrinsic radiosensitivity of 15 NSCLC lines and found the differences in gene expression levels between radiosensitive and radioresistant lines, resulting in a potentially applicable six-gene signature in NSCLC patients. The six-gene signature had the ability to predict overall survival and progression-free survival (PFS), which could translate into a prediction of the response to the cancer treatment received., [Abstract] Non-small-cell lung cancer (NSCLC) is the leading cause of cancer death worldwide, generating an enormous economic and social impact that has not stopped growing in recent years. Cancer treatment for this neoplasm usually includes surgery, chemotherapy, molecular targeted treatments, and ionizing radiation. The prognosis in terms of overall survival (OS) and the disparate therapeutic responses among patients can be explained, to a great extent, by the existence of widely heterogeneous molecular profiles. The main objective of this study was to identify prognostic and predictive gene signatures of response to cancer treatment involving radiotherapy, which could help in making therapeutic decisions in patients with NSCLC. To achieve this, we took as a reference the differential gene expression pattern among commercial cell lines, differentiated by their response profile to ionizing radiation (radiosensitive versus radioresistant lines), and extrapolated these results to a cohort of 107 patients with NSCLC who had received radiotherapy (among other therapies). We obtained a six-gene signature (APOBEC3B, GOLM1, FAM117A, KCNQ1OT1, PCDHB2, and USP43) with the ability to predict overall survival and progression-free survival (PFS), which could translate into a prediction of the response to the cancer treatment received. Patients who had an unfavorable prognostic signature had a median OS of 24.13 months versus 71.47 months for those with a favorable signature, and the median PFS was 12.65 months versus 47.11 months, respectively. We also carried out a univariate analysis of multiple clinical and pathological variables and a bivariate analysis by Cox regression without any factors that substantially modified the HR value of the proposed gene signature.

N-cadherina y FGFR1 y/o FGFR4 para uso en la predicción de la respuesta de los pacientes a un tratamiento del cáncer de pulmón y método y kit basados en dicho uso. La presente invención describe un método para predecir la respuesta de un sujeto que sufre cáncer de pulmón al tratamiento con inhibidores de FGFR. La relación de la expresión de los biomarcadores descritos con la respuesta al tratamiento, permite clasificar a los sujetos como respondedores o norespondedores al tratamiento , lo que facilita la decisión terapéutica al responsable clínico . El presente método describe los biomarcadores Ncadherina, FGFR1 y FGFR4, cómo analizarlos y cómo interpretar los resultados obtenidos , con el fin de administrar inhibidores de FGFR únicamente a los sujetos que van a responder a dicho tratamiento, optimizando el mismo, lo que permite que los sujetos no-respondedores puedan ser tratados con terapias alternativas a la de los inhibidores de FGFR.

[EN] The invention relates to a method for predicting the response of a subject suffering from lung cancer to treatment with EGFR and FGFR inhibitors, wherein said subject has not received a previous treatment with EGFR inhibitors and has not therefore developed acquired resistance to said treatment with EGFR inhibitors. The functional relationship of EGFR and FGFR receptors in the development of in vitro and in vivo tumours is described for the first time and it is demonstrated that the combination therapy of anti-EGFR and anti-FGFR drugs has a synergistic effect in patients expressing high levels of activated EGFR (pEGFR), native or mutated, as well as expressing high levels of FGFR1 and/or FGFR4, [ES] La presente invención describe un método para predecir la respuesta de un sujeto que sufre cáncerde pulmón al tratamiento con inhibidores de EGFR y FGFR, en el que dicho sujeto no ha recibido un tratamiento previo con inhibidores de EGFR y no ha desarrollado por tanto resistencia adquirida a dicho tratamiento con inhibidores de EGFR. Se describe por primera vez la relación funcional de los receptores EGFR y FGFR en el desarrollo de tumores in vitroe in vivoy se demuestra que la terapia combinada de fármacos anti-EGFR y anti-FGFR tiene un efecto sinérgico en pacientes que expresan altos niveles de EGFRactivado (pEGFR),nativo o mutado,y ademásexpresanaltos niveles de FGFR1 y/o FGFR4, [FR] La présente invention concerne une méthode de prédiction de la réponse d'un sujet, qui est atteint d'un cancer du poumon, au traitement avec des inhibiteurs de EGFR et FGFR, dans laquelle méthode ledit sujet n'a recu aucun traitement antérieur avec des inhibiteurs de EGFR et n'a pas développé ainsi de résistance acquise audit traitement avec des inhibiteurs de EGFR. On décrit pour la première fois, la relation fonctionnelle des récepteurs EGFR et FGFR dans le développement de tumeurs in vitro et on démontre que la thérapie combinée de médicaments anti-EGFR et anti-FGFR a un effet synergique chez des patients qui expriment des niveaux élevés de EGFR activé (pEGFR), natif ou muté, et qui de surcroît expriment des niveaux élevés de FGFR1 et/ou de FGFR4

[EN] The present invention describes a method for predicting the response of a subject suffering from lung cancer to treatment with FGFR inhibitors. The relationship between the expression of the biomarkers and the treatment response allows the subjects to be classified as responsive or unresponsive to the treatment, which facilitates the therapeutic decision-making of the attending clinician. The present invention also describes the biomarkers N-cadherin, FGFR1 and FGFR4, how to analyse them and how to interpret the results obtained, in order to administer FGFR inhibitors only to the subjects that are responsive to the treatment, thereby optimising same, which allows the unresponsive subjects to be treated with alternative therapies to the FGFR inhibitors., [ES] La presente invención describe un método para predecir la respuesta de un sujeto que sufre cáncer de pulmón al tratamiento con inhibidores de FGFR. La relación dela expresión de los biomarcadores descritos con la respuesta al tratamiento, permite clasificar a los sujetos como respondedores o no-respondedores al tratamiento, lo que facilita la decisión terapéutica al responsable clínico. El presente método describe los biomarcadores N-cadherina, FGFR1 y FGFR4, cómo analizarlos y cómo interpretar losresultados obtenidos, con el fin de administrar inhibidores de FGFR únicamente a los sujetos que van a responder a dicho tratamiento, optimizando el mismo, lo que permite que los sujetos no-respondedores puedan ser tratados con terapias alternativas ala delos inhibidores de FGFR., [FR] La présente invention concerne un procédé pour prédire la réponse d'un sujet atteint de cancer du poumon au traitement à l'aide d'inhibiteurs de FGFR. La relation de l'expression des biomarqueurs décrits avec la réponse au traitement permet de classer les sujets comme répondants ou non répondants au traitement, ce qui facilite la décision thérapeutique pour le responsable clinique. La présente invention décrit les biomarqueurs N-cadhérine, FGFR1 et FGFR4, comment les analyser et interpréter les résultats obtenus, afin d'administrer des inhhibiteurs de FGFR uniquement aux sujets qui répondront audit traitement, en optimisant celui-ci, ce qui permet que les sujets non répondants puissent être traités à l'aide de thérapies alternatives à celle des inhibiteurs de FGFR.

Inhibidores de FGFR para uso en el tratamiento del cáncer de pulmón. La presente invención describe un método para predecir la respuesta de un sujeto que sufre cáncer de pulmón al tratamiento con inhibidores de FGFR. La relación de la expresión de los biomarcadores descritos con la respuesta al tratamiento, permite clasificar a los sujetos como respondedores o no-respondedores al tratamiento, lo que facilita la decisión terapéutica al responsable clínico. El presente método describe los biomarcadores N-cadherina, FGFR1 y FGFR4, cómo analizarlos y cómo interpretar los resultados obtenidos, con el fin de administrar inhibidores de FGFR únicamente a los sujetos que van a responder a dicho tratamiento, optimizando el mismo, lo que permite que los sujetos no-respondedores puedan ser tratados con terapias alternativas a la de los inhibidores de FGFR.

Heat shock protein 90 (HSP90) plays an essential role in lung adenocarcinoma, acting as a key chaperone involved in the correct functioning of numerous highly relevant protein drivers of this disease. To this end, HSP90 inhibitors have emerged as promising therapeutic strategies, even though responses to them have been limited to date. Given the need to maximize treatment efficacy, the objective of this study was to use isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomic techniques to identify proteins in human lung adenocarcinoma cell lines whose basal abundances were correlated with response to HSP90 inhibitors (geldanamycin and radicicol derivatives). From the protein profiles identified according to response, the relationship between lactate dehydrogenase B (LDHB) and DNA topoisomerase 1 (TOP1) with respect to sensitivity and resistance, respectively, to geldanamycin derivatives is noteworthy. Likewise, rhotekin (RTKN) and decaprenyl diphosphate synthase subunit 2 (PDSS2) were correlated with sensitivity and resistance to radicicol derivatives. We also identified a relationship between resistance to HSP90 inhibition and the p53 pathway by glucose deprivation. In contrast, arginine biosynthesis was correlated with sensitivity to HSP90 inhibitors. Further study of these outcomes could enable the development of strategies to improve the clinical efficacy of HSP90 inhibition in patients with lung adenocarcinoma., Comunidad de Madrid, Instituto de Salud Carlos III (ISCIII)/FEDER, Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)/FEDER, Junta de Andalucía/FEDER, AECC, Depto. de Medicina, Fac. de Medicina, TRUE, pub

[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.

Introduction: There is substantial evidence for the onco- genic effects of fi broblast growth factor receptor 1 (FGFR1) in many types of cancer, including lung cancer, but the role of this receptor has not been addressed speci fi cally 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 surrogateandinteractionassays.Weperformedmono- therapy 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 ther- apy – 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 in- creases 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 pre- dict higher resistance to erlotinib or ge fi tinib 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-over expressing, 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 bene fi t 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 in- hibitors for selected patients with increased FGFR1 over- expression and EGFR activation.

Heat shock protein 90 (HSP90) is an important chaperone in lung adenocarcinoma, with relevant protein drivers such as EGFR (epidermal growth factor receptor) and EML4-ALK (echinoderm microtubule-associated protein-like protein4 fused to anaplastic lymphoma kinase) depending on it for their correct function, therefore HSP90 inhibitors show promise as potential treatments for lung adenocarcinoma. To study responses to its inhibition, HSP90 was pharmacologically interrupted by geldanamycin and resorcinol derivatives or with combined inhibition of HSP90 plus HSP70 in lung adenocarcinoma cell lines. Two-dimensional electrophoresis was performed to identify proteomic profiles associated with inhibition which will help to understand the biological basis for the responses. HSP90 inhibition resulted in altered protein profiles that differed according the treatment condition studied. Results revealed 254 differentially expressed proteins after treatments, among which, eukaryotic translation initiation factor3 subunit I (eIF3i) and citrate synthase demonstrated their potential role as response biomarkers. The differentially expressed proteins also enabled signalling pathways involved in responses to be identified; these included apoptosis, serine-glycine biosynthesis and tricarboxylic acid cycle. The proteomic profiles identified here contribute to an improved understanding of HSP90 inhibition and open possibilities for the detection of potential response biomarkers which will be essential to maximize treatment efficacy in lung adenocarcinoma.

[Objectives] Lung adenocarcinoma accounts for approximately half of lung cancer cases. Twenty to 50% of tumors of this type harbor mutations affecting epidermal growth factor receptor (EGFR) expression or activity, which can be therapeutically targeted. EGFR inhibitors in this context exhibit high efficacy and are currently used in the clinical setting. However, not all adenocarcinomas harboring EGFR mutations respond to therapy, so predictive biomarkers of therapeutic outcomes, as well as novel therapies sensitizing these tumors to EGFR inhibition, are needed., [Materials and methods] We performed in vitro gene overexpression/silencing and tumorigenic surrogate assays, as well as in vitro and in vivo combination treatments with Fibroblast Growth Factor Receptor (FGFR)/EGFR inhibitors. At the clinical level, we determined FGFR4 expression levels in tumors from patients treated with EGFR inhibitors and correlated these with treatment response., [Results] We describe a cooperative interaction between EGFR and FGFR4, which results in their reciprocal activation with pro-oncogenic consequences in vitro and in vivo. This cooperation is independent of EGFR activating mutations and increases resistance to different EGFR inhibitors. At the therapeutic level, we provide evidence of the synergistic effects of the combination of EGFR and FGFR inhibitors in high FGFR4-expressing, EGFR-activated tumors in vitro and in vivo. Correlated with these results, we found that patients treated with EGFR inhibitors relapse earlier when their tumors exhibit high FGFR4 expression., [Conclusions] We propose a novel predictive biomarker for EGFR-targeted therapy, and a highly efficacious combinatory therapeutic strategy to treat EGFR-dependent; this may may extend the use of appropriate inhibitors beyond EGFR-mutated adenocarcinoma patients.

[Introduction] FGFR4 is a tyrosine kinase receptor which, under physiological conditions, is activated upon ligand binding in a highly regulated manner. This triggers downstream signaling related to proliferation and apoptosis resistance as well as other physiological processes. Many molecular alterations of the receptor and its ligands, specially FGF19, have been reported in several types of cancer, with special relevance in hepatocellular carcinoma. In addition, these have also been detected in other solid malignancies, including lung, breast, or colon cancer, among others., [Areas covered] This review covers patent literature on specific FGFR4 inhibitors and their applications, published from 2007 to June 2018., [Expert opinion] FGFR4 inhibition has gained relevance in oncology. A considerable number of patents disclosing different approaches to inhibit this receptor have been reported, displaying promising preclinical results for different cancer models. Currently, the safety and preliminary efficacy of several small molecule inhibitors targeting FGFR4 are under early phase clinical assessment, mainly in hepatocellular carcinoma patients. If positive results are derived from these trials, they will open the door for the application of FGFR4 small molecule inhibitors to a wide population of tumors of different types that harbor FGFR4-FGF19 signaling dysregulation., [Trial registration] ClinicalTrials.gov identifier: NCT02325739., [Trial registration] ClinicalTrials.gov identifier: NCT02834780., [Trial registration] ClinicalTrials.gov identifier: NCT03144661., [Trial registration] ClinicalTrials.gov identifier: NCT02508467.

[Background] Lung cancer remains the most common cause of cancer-related death, with a 5-year survival rate of only 18%. In recent years, the development of targeted pharmacological agents and immunotherapies has substantially increased the survival of a subset of patients. However, most patients lack such efficacious therapy and are, thus, treated with classical chemotherapy with poor clinical outcomes. Therefore, novel therapeutic strategies are urgently needed. In recent years, the development of epigenetic assays and their application to cancer research have highlighted the relevance of epigenetic regulation in the initiation, development, progression and treatment of lung cancer., [Conclusions] A variety of epigenetic modifications do occur at different steps of lung cancer development, some of which are key to tumor progression. The rise of cutting-edge technologies such as single cell epigenomics is, and will continue to be, crucial for uncovering epigenetic events at a single cell resolution, leading to a better understanding of the biology underlying lung cancer development and to the design of novel therapeutic options. This approach has already led to the development of strategies involving single agents or combined agents targeting epigenetic modifiers, currently in clinical trials. Here, we will discuss the epigenetics of every step of lung cancer development, as well as the translation of these findings into clinical applications.

Background The high incidence and mortality of lung tumours is a major health problem. Therefore, the identification both of biomarkers predicting efficacy for therapies in use and of novel efficacious therapeutic agents is crucial to increase patient survival. MAP17 (PDZK1IP1) is a small membrane-bound protein whose upregulation is reported as a common feature in tumours from diverse histological origins. Furthermore, MAP17 is correlated with tumour progression. Go to: Methods We assessed the expression of MAP17 in preclinical models, including cell lines and patient-derived xenografts (PDXs), assessing its correlation with sensitivity to different standard-of-care drugs in lung adenocarcinoma, as well as novel drugs. At the clinical level, we subsequently correlated MAP17 expression in human tumours with patient response to these therapies. Go to: Results We show that MAP17 expression is induced during lung tumourigenesis, particularly in lung adenocarcinomas, and provide in vitro and in vivo evidence that MAP17 levels predict sensitivity to therapies currently under clinical use in adenocarcinoma tumours, including cisplatin, carboplatin and EGFR inhibitors. In addition, we show that MAP17 expression predicts proteasome inhibitor efficacy in this context and that bortezomib, an FDA-approved drug, may be a novel therapeutic approach for MAP17-overexpressing lung adenocarcinomas. Go to: Conclusions Our results indicate a potential prognostic role for MAP17 in lung tumours, with particular relevance in lung adenocarcinomas, and highlight the predictive pot0065ntial of this membrane-associated protein for platinum-based therapy and EGFR inhibitor efficacy. Furthermore, we propose bortezomib treatment as a novel and efficacious therapy for lung adenocarcinomas exhibiting high MAP17 expression.

Lung tumors represent a major health problem. In early stage NSCLC tumors, surgical resection is the preferred treatment, but 30-55% of patients will relapse within 5 years after surgery. Thus, the identification of prognostic biomarkers in early stage NSCLC patients, especially those which are therapeutically addressable, is crucial to enhance survival of these patients. We determined the immunohistochemistry expression of key proteins involved in tumorigenesis and oncogenic signaling, p53, EGFR, pAKT and pERK, and correlated their expression level to clinicopathological characteristics and patient outcome. We found EGFR expression is higher in the squamous cell carcinomas than in adenocarcinomas (p=0.043), and that nuclear p53 staining correlated with lower differentiated squamous tumors (p=0.034). Regarding the prognostic potential of the expression of these proteins, high pERK levels proved to be an independent prognostic factor for overall (p<0.001) and progression-free survival (p<0.001) in adenocarcinoma patients, but not in those from the squamous histology, and high p53 nuclear levels were identified as independent prognostic factor for progression-free survival (p=0.031) only in squamous cell carcinoma patients. We propose a role as early prognostic biomarkers for pERK protein levels in adenocarcinoma, and for nuclear p53 levels in squamous cell lung carcinoma. The determination of these potential biomarkers in the adequate histologic context may predict the outcome of early stage NSCLC patients, and may offer a therapeutic opportunity to enhance survival of these patients.

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.