Viral Particle-Mediated SAMHD1 Depletion Sensitizes Refractory Glioblastoma to DNA-Damaging Therapeutics by Impairing Homologous Recombination.

Abstract

Simple SummaryGlioblastoma (GBM) is a lethal and common primary brain tumor that accounts for about 50% of all diagnosed malignant gliomas. Despite aggressive standard-of-care treatment of surgical resection followed by γ-irradiation (IR) and DNA alkylating agent temozolomide (TMZ), the average post-diagnosis survival time for a GBM patient remains at 15 months. This is mainly due to acquired resistance and limited therapeutic options. Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) supports DNA double-strand break repair by promoting homologous recombination (HR) and it can be targeted to proteasomal degradation by viral protein X (Vpx). We aim to evaluate whether depleting SAMHD1 sensitizes refractory GBM to IR and TMZ, and the possibility of utilizing Vpx as therapeutic tool. We report that SAMHD1 is highly expressed in GBM. Vpx-mediated SAMHD1 depletion impaired HR and sensitized GBM cells to IR and TMZ. Our finding demonstrates the potential therapeutic benefit of targeting SAMHD1 with Vpx in GBM.The current standard-of-care treatment for glioblastoma includes DNA damaging agents, γ-irradiation (IR) and temozolomide (TMZ). These treatments fail frequently and there is limited alternative strategy. Therefore, identifying a new therapeutic target is urgently needed to develop a strategy that improves the efficacy of the existing treatments. Here, we report that tumor samples from GBM patients express a high level of SAMHD1, emphasizing SAMHD1’s importance. The depletion of SAMHD1 using virus-like particles containing Vpx, VLP(+Vpx), sensitized two independent GBM cell lines (LN-229 and U-87) to veliparib, a well-established PARP inhibitor, and slowed cell growth in a dose-dependent manner. In the mouse GBM xenograft model, Vpx-mediated SAMHD1 depletion reduced tumor growth and SAMHD1 knockout (KO) improved survival. In combination with IR or TMZ, SAMHD1 KO and exposure to 50% growth inhibitory dose (gID50) of VLP(+Vpx) displayed a synergistic effect, resulting in impaired HR, and improved LN-229 cells’ sensitivity to TMZ and IR. In conclusion, our finding demonstrates that SAMHD1 promotes GBM resistance to treatment, and it is a plausible therapeutic target to improve the efficacy of TMZ and IR in GBM. Furthermore, we show that Vpx could be a potential therapeutic tool that can be utilized to deplete SAMHD1 in GBM.