Abstract B025: Elucidating the role of ZFTA-RELA in radiation resistance in ependymoma

Abstract Treatments for childhood brain cancer, the leading cause of disease mortality in children, has not changed in the last three decades and constitutes surgery combined with cytotoxic chemo- and radio- therapy. RT is not always curative, and the mechanisms that promote resistance to radiation for many childhood cancers remains elusive. We found the ZFTA-RELA (ZR) fusion oncoprotein (FO), a potent driver of Ependymoma (EPN), drives a radio-resistant phenotype, but the mechanism underlying this observation is unknown. We hypothesized that radio-resistance mediated by ZR arises from direct ZR driven transcription. Analysis of numerous mouse and human datasets reveals ZR upregulates pathways associated with radio-resistance. We demonstrate the importance of ZR transcriptional programs on radiosensitivity by abrogating the DNA binding ability of ZR to sensitize EPN cells to RT. To identify ZR target genes that mediate radiosensitivity, we performed CRISPR-Cas12 dropout screens in both mouse and human EPN cell lines and identified >150 genes that sensitize EPN to RT, including canonical regulators of homologous recombination repair and the NFKβ pathway. In parallel, we performed high throughput drug screening to identify pharmacologic radiosensitizers in EPN and identified several combinations containing PARP1 inhibitors that are effective in vitro and tolerable in vivo. These data represent novel efforts to identify genetic and chemical radiosensitizers in EPN, and demonstrate how fusion oncoproteins like ZR hijack normal transcriptional programs to promote resistance to conventional therapy. Citation Format: Blake Holcomb, Ha Won Lee, Pete Hall, Shilpa Narina, Amanda Bland, Siri Ippagunta, Tuyu Zheng, Amir Arabzade, Nic Laboe, Patrick Connelly, Shondra Miler, Taosheng Chen, Stephen Mack. Elucidating the role of ZFTA-RELA in radiation resistance in ependymoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl):Abstract nr B025.