EXTH-74. ATR INHIBITION IN EXPERIMENTAL GLIOMA

Abstract Glioblastoma are incurable primary tumors of the central nervous system. Novel treatment options urgently needed. Recently, we investigated molecular effects disrupting (b)HLH network, a frequently altered and tumor-promoting transcriptional network in glioma, by introducing dominant-negative variant E47 protein. The identified downstream anti-tumor included DNA damage response pathway. In present study, aimed at investigating anti-glioma ATR inhibition vitro vivo with particular focus on treatment-induced vulnerabilities potential combination therapies. We performed acute cytotoxicity, clonogenic survival assays, flow cytometry-based determination cell cycle status apoptosis induction human murine glioma lines vitro, tumor growth SMA560/VMDk syngeneic mouse model vivo. Furthermore, applied RNA sequencing, DigiWest protein profiling analyses genome-wide CRISPR/Cas9 loss-of function activation screens to determine Combination treatments were further analyzed for synergism Bliss ZIP synergy models. cells resulted reduced viability survival. However, differential patterns gene expression deregulation (e.g. p53 signaling) differing modes arrest distinct systems argue substantial heterogeneity regard inhibition. Based our data designed combinatorial treatments. will novel insights into promising using their underlying mechanisms.