2. Academic Validation
  3. RNaseH2 inhibition potentiates temozolomide response in patient derived glioblastoma cells

RNaseH2 inhibition potentiates temozolomide response in patient derived glioblastoma cells

  • Sci Rep. 2025 Nov 24;15(1):41486. doi: 10.1038/s41598-025-25298-5.
Miroslava Kissova 1,  Judit Martinez Segarra # 1,  Tobias Solli Iveland # 1 2,  Marthe Vestvik 1,  Erlend Ravlo 1,  Wei Wang 1,  Lars Hagen 3,  Nina-Beate Liabakk 1,  Maria Camara-Quilez 1,  Miquel Arano Barenys 1,  Ole Solheim 4 5,  Bård Helge Hoff 6,  Eirik Sundby 7,  Magnar Bjørås 1 8 9,  Geir Slupphaug 1 10 3,  Torkild Visnes 11,  Alessandro Brambilla 12 13 14
Affiliations

Affiliations

  • 1 Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology NTNU, Trondheim, 7491, Norway.
  • 2 Department of Oncology, Akershus University Hospital, Lørenskog, 1478, Norway.
  • 3 PROMEC Core Facility for Proteomics and Modomics, Norwegian University of Science and Technology, NTNU, and the Central Norway Regional Health Authority Norway, Trondheim, 7491, Norway.
  • 4 Department of Neuromedicine and Movement Science, NTNU, Trondheim, Norway.
  • 5 Department of Neurosurgery, St. Olavs University Hospital, Trondheim, Norway.
  • 6 Department of Chemistry, Faculty of Natural Sciences, Norwegian University of Science and Technology NTNU, Trondheim, Norway.
  • 7 Department of Material Science, Norwegian University of Science and Technology, NTNU, Trondheim, 7491, Norway.
  • 8 Department of Microbiology, Oslo University Hospital and University of Oslo, Oslo, Norway.
  • 9 Center of Embryology (CRESCO), University of Oslo, Oslo, 0313, Norway.
  • 10 Clinic of Laboratory Medicine, St. Olavs Hospital, Trondheim, 7491, Norway.
  • 11 Department of Biotechnology and Nanomedicine, SINTEF Industry, Trondheim, Norway. [email protected].
  • 12 Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology NTNU, Trondheim, 7491, Norway. [email protected].
  • 13 Clinic of Laboratory Medicine, St. Olavs Hospital, Trondheim, 7491, Norway. [email protected].
  • 14 PROMEC Core Facility for Proteomics and Modomics, Norwegian University of Science and Technology, NTNU, and the Central Norway Regional Health Authority Norway, Trondheim, 7491, Norway. [email protected].
  • # Contributed equally.
PMID: 41285884 DOI: 10.1038/s41598-025-25298-5
Abstract

Glioblastoma (GBM) is the most common and lethal form of primary brain tumor, characterized by poor prognosis and limited treatment options, with a median survival of only 12 to 15 months post-diagnosis. Despite standard therapeutic protocols involving temozolomide (TMZ) and radiotherapy, effective treatment is challenging, underscoring the need to explore alternative therapeutic strategies. One promising approach is the inhibition of DNA damage response (DDR) pathways. RNaseH2, a key enzyme involved in ribonucleotide excision repair (RER), plays a critical role in maintaining genomic stability by removing ribonucleotides misincorporated into DNA. Thus, inhibition of RNaseH2 may enhance tumor mutational burden (TMB) and potentially transform immunogenically "cold" tumors into immunogenically "hot" tumors. In this study, a high-throughput screening (HTS) assay resulted in the identification of 52 potential RNaseH2 inhibitors from a library of 71227 compounds. We selected six of these inhibitors for further investigation, evaluating their effects both alone and in combination with TMZ in commercially available U87 MG wild-type and IDH1 mutant (IDH1 WT and MUT) glioma cells and patient-derived cells established from glioma organoids (GBO-PDC). This study highlights the therapeutic potential of RNaseH2 inhibition in combination with TMZ for GBM therapy, validated in patient-derived model, offering a promising avenue for treating this highly aggressive and yet uncurable Cancer.

Keywords

Drug screening; GBM; High-throughput screening (HTS).

Figures
Products