P08.18 Replication stress as a driver of genomic instability in malignant gliomas

Abstract

AbstractGlioblastoma (GBM, WHO grade IV astrocytoma) is among the deadliest of solid tumors with median survival rates of only approximately 15 months. In spite of concerted efforts, molecular mechanisms/genes causing high recurrence and treatment resistance are poorly understood. The tumor suppressor BRCA1 plays a critical role in maintaining genomic stability, in general, and replication stress (RS), in particular. Numerous reports have demonstrated that wild type BRCA1 loss impairs the growth of several cancers (breast, ovarian, lung, prostate and colon). Our data show considerably higher level of RS in malignant gliomas compared to other solid tumors (breast, prostate ovarian) and identify a novel role for BRCA1, where high BRCA1 expression negatively associates with glioma patient survival. BRCA1 plays an unexpected tumor-promoting role in GBM, safeguarding a protective response to supraphysiological RS levels via transcriptional regulation of RRM2 expression. shRNA-mediated knockdown of BRCA1 or chemical inhibition of RRM2 both induce GBM cell death due to accumulation of RS-induced DNA damage in vitro and extend survival of tumor bearing mice in vivo, highlighting the clinical relevance of our findings. Acknowledgements: This work was supported by Danish Cancer Society Foundation.