Abstract 3068: The clonal nature of FGFR3-TACC3 in glioma: Mechanism discovery and preclinical study

Abstract During the course of treatment, tumor cells can undergo a Darwinian process of clonal evolution, where resistant cell clones emerge, proliferate and replace more vulnerable ones, ultimately leading to increased treatment resistance. Numerous oncogenic fusion genes have recently been identified in gliomas, promoting malignant transformation and serving as potential therapeutic targets. Among these, the FGFR3-TACC3 (F3-T3) fusion gene was initially detected in glioblastoma multiforme (GBM), with its fusion protein comprising primarily FGFR3 structural domains and a smaller portion of TACC3. F3-T3 fusions are consistently expressed in both untreated and recurrent tumors, confirming the clonal persistence of these fusion events. Our previous study implicated F3-T3 in chemotherapy resistance in GBM, though the underlying mechanism remained unclear. In this study, we further investigate the clonal nature and functional role of F3-T3 in GBM cells. Through bioinformatics data mining, we discovered that F3-T3 functionally enriches DNA repair pathways, as shown by Gene Set Enrichment Analysis (GSEA). Experimental results demonstrated that GBM cells harboring F3-T3 maintain their proliferation, invasion and migration capabilities under temozolomide (TMZ) treatment. Subsequent RNA sequencing revealed activation of the PI3K-AKT signaling pathway in F3-T3 GBM cells under TMZ conditions. Further analysis identified PKM2 as a downstream substrate of the F3-T3 protein, linking it to the DNA damage response. Experimental evidence highlights the critical role of the F3-T3/PI3K-AKT/PKM2 axis in mediating chemoresistance in F3-T3 GBM. Importantly, our preclinical models demonstrated synergistic efficacy when combining TMZ with either FGFR or PI3K inhibitors in F3-T3 GBM. In summary, our findings underscore the significance of the F3-T3/PI3K-AKT/PKM2 axis in driving chemotherapy resistance in F3-T3 GBM and present a potential therapeutic strategy for gliomas with F3-T3 fusions, providing empirical support for future fusion gene-targeted investigations. Citation Format: Yiming Li, Tao Li, Xiude Ren, Jianshen Liang, Jikang Fan, Xisen Wang, Shengping Yu, Wei Zhang, Xuejun Yang. The clonal nature of FGFR3-TACC3 in glioma: Mechanism discovery and preclinical study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3068.