TMIC-41. ARGININE DEPRIVATION ALTERS DNA DAMAGE RESPONSE IN ARGINOSUCCINATE SYNTHETASE NEGATIVE GLIOBLASTOMA AND POTENTIATES STANDARD OF CARE

Abstract

Abstract Glioblastoma (GBM) is the most aggressive and prevalent primary brain malignancy with an average life expectancy of 18 months despite the standard of care which includes resection, temozolomide and radiotherapy. Thirty percent of GBMs show transcriptional loss of arginosuccinate synthetase 1 (ASS1), displaying arginine auxotrophy and hence, are amenable to arginine deprivation therapy by ADI-PEG20. Moreover, these tumours are more aggressive than their non-arginine auxotrophic counterparts. In this study we demonstrate that this may lie in part due to their enhanced ability to repair damaged DNA. ADI-PEG20 significantly altered the expression of DNA repair genes in vitro and in vivo. We observed downregulation of PCNA, ATR (p=0.0063) and CHEK1 (p=0.0150) and upregulation of CHEK2 (p=0.0033) and RAD51 (p=0.0230). PARP1 was also downregulated, albeit not statistically significant. Addition of ADI-PEG20 to temozolomide and radiation also caused significant downregulation of BRCA1 (p=0.0340) . With DNA repair gene upregulation contributing to treatment resistance and DDR inhibitors shown to potentiate current therapies in the literature, not only do our results help elucidate the mechanisms of radiosensitisation with ADI-PEG20, targeting this pathway with DDR inhibitors alongside the pleiotropic effects of ADI-PEG20 may provide a novel therapeutic combination for ASS1 negative GBM.