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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Interleukin-11 (IL11) has been associated with tumorigenesis in a wide variety of tumors, including lung cancer, and it has been proposed as a diagnostic biomarker for lung adenocarcinoma. However, it is still not clear how IL11 affects the tumorigenesis. It is possible that, as other cytokines, it has a dual role in the tumor cell and tumoral microenvironment. Thus, the inhibition of IL11 could be an interesting therapeutic option to test in these patients. First, we confirmed the pro-tumorigenic effect of IL11 in patients and mouse models of lung adenocarcinoma (cancer cell lines xenografts, patient derived xenografts; PDXs and genetically engineered mouse models; GEMMs). Later, we knocked-down the expression of IL11 or its specific receptor IL11RA in adenocarcinoma cell lines in order to analyze their tumorigenic properties in vitro and in vivo. We confirmed that fibroblasts are a relevant source of IL11, so we knocked-down IL11 expression in order to analyze how it affects the fibroblasts´ properties, including the secretion of other pro-tumorigenic cytokines and growth factors. We reported that an increased expression of IL11 correlates with a poorer survival in lung adenocarcinoma patients and that IL11 stimulation increases the proliferation rates in xenografts, PDXs and GEMMs. On the contrary, IL11 or IL11RA knockdown in adenocarcinoma cell lines reduces their pro-tumorigenic properties in vitro and in vivo. Finally, the silencing of IL11 in fibroblasts reduces their proliferation, migration and secretion of pro-tumorigenic cytokines and growth factors. In conclusion, we propose that IL11 plays a direct pro-oncogenic role in lung adenocarcinoma tumoral cell and an indirect role in tumoral microenvironment. The genetic ablation of IL11 has an anti-tumoral effect, so it could be interesting to develop a pharmacological tool which neutralizes the IL11-IL11RA signaling to test as a therapeutic strategy in preclinical models. Thus, IL11 could represent a potential therapeutic target that deserves to be more exhaustively studied in the clinical settings. Citation Format: Laura Ojeda, Cristina Cirauqui, Sonia Molina-Pinelo, Eva M Garrido-Martín, Javier Ramos-Paradas, Patricia Yagüe, Alba Santos, Nuria Carrizo, Ana B. Enguita, Maria Teresa Muñoz, Jose Luis Solorzano, Luis Paz-Ares, Irene Ferrer. Interleukin-11 could be a novel therapeutic target for lung adenocarcinoma patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5247.

Background: The use of good preclinical models is essential in translational cancer research. An appropriate preclinical model must be useful for drug screening, biomarker discovery and preclinical evaluation of precision therapeutic strategies. Conventional available preclinical models are not optimal to this end. Xenografts from cell lines do not reconstitute the architecture and environment of human cancer and acquire mutations not found in the original tumor. Our aim is to generate and characterize a collection of PDX models for translational lung cancer research by implantation of lung primary human tumors in mice. Mainly, this collection will be used for biomarker identification and preclinical evaluation of new therapeutic strategies targeted to bad prognostic lung tumors with suboptimal therapeutic approaches.Methods: Resected NSCLC from patients were subcutaneous xenografted and expanded in successive groups of nude mice to get a perpetual live bank of each tumor. Every tumor, which successfully grew in mice, was used to analyze the exome and transcriptome by NGS techniques. Furthermore, a bank of frozen pieces of tumor was stored in order to generate later cohorts of tumor-bearing mice suitable for preclinical drug evaluation and biomarker identification. Results: We have characterized 32 different PDX models at the genomic and transcriptomic level: 20 SCC, 10 ADC and 2 LCC. The PDX models mostly retain the principal histologic and molecular characteristics of their donors and recapitulate the heterogeneity of human lung tumors. In our PDX collection we have sufficiently represented all the NSCLC histology and the most relevant molecular alterations in lung cancer in order to perform precision medicine evaluation studies. Conclusions: We have generated and characterize a collection of PDX models of NSCLC, which represents the most frequent histological and molecular subtypes of this type of LC. This collection will be really useful to integrate drug screening with biomarker discovery and to evaluate precision therapeutic strategies preclinically. Our future aim will be to use this collection in order to identify new effective therapeutic strategies targeted to bad prognostic subtypes of lung cancer. Legal entity responsible for the study: IF is funded by Fundacion AECC and Consejería de Salud de la Junta de Andalucía (PI-0029-2013). SMP is funded by Consejería de Salud y Bienestar Social (PI-0046-2012), and Fundación Mutua Madrileña (2014). LPA is funded by Fondo de Investigación Sanitaria (1401964) and RTICC (R12/0036/0028).

Lung cancer is the leading cause of cancer-related deaths worldwide. KRAS is the most frequent mutated driver gene in NSCLC but today has no effective treatments. Therefore, there is an urgent unmet need to find a tailored treatment alternative in the clinic. We need experimental models which really predict the efficacy of these alternative treatments. PDX and organoids are models that recapitulate more accurately the complexity of human cancer, therefore they are the best models we can use to address such clinically relevant questions. We aim to generate and characterize both NSCLC PDX, and PDX-derived organoids (PDXDOs) collections to perform preclinical assays, address to find alternative therapies for KRAS-mutant lung cancer. Among these therapeutic strategies we evaluated the efficacy of CDK4 inhibitors (CDK4i) in combination with ERK1/2 inhibitors (ERK1/2i). We studied the mechanism of action of the drugs in combination and identified possible predictive response biomarkers by RNAseq. We have established and characterized a collection of 45 NSCLC PDX models derived from early-stage patients, eight of them with KRAS mutations. All retained the principal histologic and molecular characteristics of their donors during the passages. We have also generated a collection of 15 PDXDOs, which maintained the same characteristics of their PDX donors. We evaluate the efficacy of CDK4i in monotherapy and in combination with ERK1/2i in KRAS-mutated models. In vitro, using PDXDOs, the therapeutic combination tested reduced viability and downregulated signaling pathways involved in cell progression, this effect was observed in all PDXDO models tested, including those that were primary resistant to CDK4i in monotherapy. Similarly, in vivo, using the PDX models, the therapeutic combination tested produced a significant reduction in tumor growth compared to the drugs in monotherapy. The transcriptomic analysis showed CDK4i inhibited cell-cycle processes, whereas the combination therapy resulted in an increased inhibition and also reversed the CDK4i-mediated activation of PI3K or WNT pathways, which would explain the synergistic effect of the combination. In conclusion, we have established a collection of 45 NSCLC PDX models and 15 PDXDOs, which allow to evaluate (in vitro and in vivo) the therapeutic efficacy of different drug combinations targeting different driver genes mutated such KRAS, which today has no effective treatments. These preclinical models will be really useful to integrate drug screening with biomarker discovery. Using our collections, we have demonstrated the combination of CDK4i with ERK1/2i was more effective than the drugs in monotherapy, even for those cases which primary showed CDK4i-resistance. Therefore, we propose this therapeutic combination as a good therapeutic strategy to test in the clinic. Citation Format: Patricia Yagüe, David Gomez, Álvaro C Ucero, Laura García, Patricia Plaza, Nuria Carrizo, José Luis Solorzano, Luis Paz-Ares, Irene Ferrer. Evaluation of novel therapeutic strategies for KRAS mutated NSCLC patients using our own collections of PDX and PDX-derived organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3101.