Arginine deprivation enhances ASS1-negative glioblastoma radiosensitivity via epigenetic silencing of DNA repair genes

Glioblastoma (GBM) is the most aggressive form of primary brain cancer, with a poor survival. Currently, patients with GBM are treated with surgery followed by adjuvant radiotherapy and temozolomide, both of which are DNA damaging agents. However, this regimen exhibits limited efficacy, with high rates of recurrence and treatment resistance. This underscores the urgent need to identify novel and more effective therapeutic strategies or methods to enhance the efficacy of standard approaches to improve patients' outcome and prevent recurrence. By integrating data from the Chinese Glioma Genome Atlas (CGGA) database and our own RNA sequencing analysis of 23 clinical samples, we found that low ASS1 expression correlates with increased DNA damage repair capacity and poorer prognosis in ASS1-negative GBM. Arginine deprivation via ADI-PEG20 selectively inhibited proliferation of ASS1-negative GBM cells and amplified radiotherapy-induced DNA damage, which intensified within 30 minutes and peaked at 1 hour. Mechanistically, in both ASS1-negative patient-derived tumor cells and a patient-derived xenograft (PDX) model, ADI-PEG20 downregulated DNA repair genes, namely poly ADP-ribose polymerase 1 (PARP1) and DNA ligase 1 (LIG1), at the epigenetic level by upregulating the repressive H3K27me3 histone marker. Collectively, our findings demonstrate that arginine deprivation is an effective strategy to enhance the radiosensitivity of ASS1-negative GBM and suggest that combination therapy with PARP inhibitors should be explored.