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

Waaqo Daddacha, Dominique Monroe, Kristen Carver, Edidiong R. Usoro, Ahmet Alptekin, Hongyan Xu, Satoru Osuka, Ali S. Arbab, Daitoku Sakamuro

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number4490
JournalCancers
Volume14
Issue number18
DOIs
StatePublished - Sep 2022

Keywords

  • DNA damage
  • DNA repair
  • SAMHD1
  • TMZ
  • Vpx
  • glioblastoma
  • homologous recombination
  • irradiation
  • malignant glioma
  • radiation therapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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