Abstract 4489: N-Cadherin acts as a predictive biomarker for anti-FGFR therapy in KRAS wild-type NSCLC

Abstract

Abstract Background: Lung cancer is the leading cause of cancer-related deaths worldwide. FGFR1 has been associated with tumorigenesis in a variety of tumor types, including lung cancer. As a therapeutic approach, their inhibition has been attempted and was initially focused on FGFR1-amplified tumors, though with limited success. Preliminary data of our group suggests that N-Cadherin play a key role for the oncogenicity of FGFR1 and predict FGFR-targeted therapy efficacy in Non-small cell lung cancer (NSCLC). However, it is possible that other biomarkers, together with N-Cadherin, can determine the response to anti-FGFR therapy. Therefore, it is essential the identification of new biomarkers that could help to predict more accurately those patients that could benefit from anti-FGFR therapy. Materials and Methods: We have treated 15 NSCLC PDX models with high FGFR1 expression levels and variable N-Cadherin expression levels, with the FGFR inhibitor (FGFRi) AZD4547. Based on their sensitivity to treatment, the PDX models were classified into two groups: Responders and Non-responders. All PDX models were characterized at the proteomic, genomic, and transcriptomic levels by western blot, whole exome sequencing, and RNA-Seq, respectively, and we used this information for defining the responder versus the non-responder group. Subsequently, the GDSC repository was used to validated our data in a cohort of lung adenocarcinoma (LUAD) cell lines. Results: Responder and non-responder groups revealed a distinct pattern of genomic alterations and gene expression profile. As expected, GSEA identified an enrichment in Responders group of pathways related to FGFR1 signaling and ECM proteins, among them N-Cadherin stands out. Moreover, we observed an enrichment of KRAS mutations and genes related to the KRAS signature and to the intrinsic resistance to FGFRi in the non-responder group. To validate our findings and using the GDSC repository, we observed an enriched resistance to inhibitors of FGFR1 signaling in a cohort of KRAS mutant LUAD cell lines. Furthermore, we confirm a tendency for increased sensitivity in high N-Cadherin expressing cell lines, but only in KRAS wildtype context. Conclusions: In conclusion, previous research had underlined N-Cadherin as a potential biomarker of response to FGFRi, while not successful in all contexts. Transcriptome study of PDXs classified as responder or non-responder to FGFRi revealed a differential gene expression pattern, with an upregulation of N-Cadherin pathway observed in the Responder group, while an enrichment of KRAS signaling and KRAS mutations in non-Responders. Furthermore, we validated our finding using a cell line repository that confirm that N-Cadherin could predict FGFR-targeted therapy efficacy but only in the KRAS wildtype context. Citation Format: Santiago G. Borrego, Cristina Cirauqui, David Gómez-Sánchez, Haiyun Wang, Alicia Luengo, Chiara Ambrogio, Luis Paz-Ares, Irene Ferrer. N-Cadherin acts as a predictive biomarker for anti-FGFR therapy in KRAS wild-type NSCLC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4489.