DNAR-08. THE ROLE OF SMARCAL1 AS A SYNTHETIC LETHAL VULNERABILITY IN ATRX-DEFICIENT GLIOMAS

Abstract Mechanisms to maintain telomere length over successive cell divisions are a requirement for cancer immortalization. Although many cancers through the activation of telomerase, ~10-15% human use telomerase-independent mechanisms maintenance, termed Alternative Lengthening Telomeres (ALT). In gliomas, ALT phenotype is associated with loss-of-function mutations in ATRX gene IDH-mutant astrocytomas, adult and pediatric glioblastomas (GBM), high-grade astrocytomas piloid features, pleomorphic xanthoastrocytomas. GBM, we previously identified relatively rare subset ALT-positive wildtype tumors that harbored SMARCAL1 gene, found loss activity plays causative role onset these tumors. an annealing helicase localizes sites DNA damage replication stress catalyzes reversal stalled forks. To better understand relationship between mutations, activity, phenotype, investigated localization function glioma cells xenografts native deficiency. We ALT-associated PML bodies astrocytoma lines concurrent IDH1 (derived from grade 3 4 tumors). Our data show inducible suppression via doxycycline-induced RNAi leads increased double-strand breaks, abundance extrachromosomal telomeric repeats (c-circles), sensitivity irinotecan, topoisomerase I inhibitor. orthotopic mouse model, depletion exhibited chemosensitizing effect combination irinotecan against patient-derived xenograft (astrocytoma, Grade 4). Based on data, hypothesize critical resolving ATRX-deficient malignant gliomas. therefore propose functions as synthetic lethal vulnerability gliomas inhibition viable therapeutic strategy