ATRT-12. EXPLORING FGFR INHIBITION AND COMBINATION THERAPIES FOR ATYPICAL TERATOID/RHABDOID TUMORS

Abstract

Abstract BACKGROUND Atypical teratoid/rhabdoid tumors (ATRTs) are aggressive pediatric brain neoplasms characterized by an inactivation of the SWI/SNF chromatin remodeling complex members SMARCB1 or SMARCA4. Based on epigenetic profiling ATRTs can be divided into four different molecular subgroups. Despite improvements in treatment strategies, the prognosis for ATRT patients remains dismal. The FGF/FGFR signaling pathway plays a crucial role in many physiological processes, including embryonic development, tissue repair, angiogenesis. Dysregulation of the signaling axis is driving tumorigenesis. Targeted therapeutic approaches, particularly FGFR inhibitors, have demonstrated potential in enhancing treatment outcomes for various tumors, including pediatric brain tumors. METHODS We used bulk and single-cell RNA sequencing (scRNA-seq) data to examine the expression patterns of FGF family members in ATRTs. Subsequently, we conducted in vitro analysis on a panel of FGFR inhibitors and combination treatments. RESULTS Transcriptomic analysis of more than 130 ATRT tissues samples, revealed a widespread expression of FGFR1 and FGFR2 across all ATRT subtypes. Notably, FGFR1 displayed distinctly elevated expression in ATRT-SHH, surpassing levels seen in other ATRT subtypes and brain tumor types. Utilizing scRNA-seq data of murine ATRT models, we elucidated an autocrine FGFR signaling loop. To assess the therapeutic feasibility of targeting FGFR, we evaluated a panel of FGFR inhibitors, currently in clinical development, across 10 in house established patient-derived cell models (6 ATRT-MYC, 3 ATRT-SHH, 1 ATRT-TYR), revealing sensitivity in a nanomolar to a low-micromolar range. We further explored combination therapies, demonstrating that Erdafitinib, the most effective inhibitor when combined with Abemaciclib and radiation, exhibited enhanced synergistic effects in 2D as well as in 3D tumoroid models. Investigations towards testing these combinations in an organoid co-culture system, along with in vivo models are ongoing. CONCLUSIONS This study emphasizes the prospect of combining FGFR inhibition with radiation and CDK4/6 inhibition as a therapeutic target for ATRTs.