Abstract 208: FGFR2 splice variant as a cell fate adjudicator determines clinical outcomes in non-small cell lung cancer

Abstract The splice variants specific protein expression in tumor cells presents promising targets for cancer therapy. The concept is supported by the recent introduction of the splice variant-specific antibody against FGFR2 IIIb (FGFR2b) in gastric cancer. Indeed, signaling of the two FGFR2 splice variants FGFR2b and FGFR2 IIIc (FGFR2c), whose expression is mutually exclusive on a cellular level, is mediated by different ligands and distinct downstream responses that can contribute to many aspects of tumorigenesis. Our study aimed to characterize the expression FGFR2b and 2c in non-malignant lung and non-small cell lung cancer (NSCLC) tissue and relate splice variant-specific expression to the histological and molecular background of cancer and its clinical impact.FGFR2b/FGFR2c isoforms expression was determined in RNA-seq data from 180 NSCLC patients and 19 tissues from normal lung (patient-matched). Cell-type specific expression and pan-cancer analysis of FGFR2 were explored using a public database, including DBTSS (NSCLC: 26, normal lung epithelium: 1, normal lung fibroblast 1) and CCLE (Total: 1019, NSCLC: 131), GTEx (normal lung tissue: 578) and HPA (scRNAseq for lung).Our results confirm a cell-specific expression in normal cells with dominance of FGFR2b in epithelial cells and FGFR2c in mesenchymal cells. In normal lung tissue, the FGFR2b variant showed high abundance. Pan-cancer analysis revealed FGFR2c dominant cancers (e.g., CNS tumors, kidney, liver) as well as FGFR2b dominant cancer types (e.g., breast, colon, lung cancer). The RNAseq data from our NSCLC cohort showed a chief expression of FGFR2b in 116 cases (64%), FGFR2c in 31 cases (17%), and a mixed FGFR2c/FGFR2b transcriptomics (18%). The ratio of FGFR2b/FGFR2c as a metric for splice variant dominance was associated with squamous histology, higher stage, and KRAS mutations. Differential gene expression analysis of cancer tissue and cell lines revealed an association of the splice variant FGFR2c to epithelial-mesenchymal transition (EMT) and the regulation of genes (ZEP1, ERSP1, CDH1) involved in the TGF-beta signal pathway. Finally, the ratio of FGFR2b/FGFR2c demonstrated a strong association with overall survival in NSCLC patients with the FGFR2c variant as unfavorable predictors (High vs low ratio, p = 0.01). Our study indicates cell-specific splice variant expression in non-malignant and malignant cells. The prognostic unfavorable impact of the FGFR2c variant on NSCLC patient survival might be explained by its association with TGF signaling and EMT. The observed clinical and biological difference between FGFR2b and FGFR2c dominated cancers gives further rationale to exploit splice variants as therapeutical targets. Citation Format: Hui Yu, Masafumi Horie, Amanda Lindberg, Max Backman, Neda Hekmati, Johanna Mattsson, Naoya Miyashita, Hans Brunnström, Fredrik Ponten, Akira Saito, Carina Strell, Patrick Micke. FGFR2 splice variant as a cell fate adjudicator determines clinical outcomes in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 208.