Abstract
Mathew Lozinski2,3,4, Nikola A. Bowden2,3, Moira C. Graves2,3,4, Michael Fay2,3,4,5, Bryan W. Day6, Brett W. Stringer7 and Paul A. Tooney1,3,4
1 School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, NSW, Australia
2 School of Medicine and Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, NSW, Australia
3 Drug Repurposing and Medicines Research Program, Hunter Medical Research Institute, New Lambton, NSW, Australia
4 Mark Hughes Foundation Centre for Brain Cancer Research, University of Newcastle, NSW, Australia
5 GenesisCare, Newcastle, NSW, Australia
6 QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
7 Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD, Australia
Correspondence to:
Paul A. Tooney, | email: | paul.tooney@newcastle.edu.au |
Keywords: glioblastoma; DNA damage response; ataxia-telangiectasia and rad3-related protein; radiation therapy; temozolomide
Received: November 06, 2023 Accepted: December 28, 2023 Published: January 16, 2024
ABSTRACT
Glioblastoma cells can restrict the DNA-damaging effects of temozolomide (TMZ) and radiation therapy (RT) using the DNA damage response (DDR) mechanism which activates cell cycle arrest and DNA repair pathways. Ataxia-telangiectasia and Rad3-Related protein (ATR) plays a pivotal role in the recognition of DNA damage induced by chemotherapy and radiation causing downstream DDR activation. Here, we investigated the activity of gartisertib, a potent ATR inhibitor, alone and in combination with TMZ and/or RT in 12 patient-derived glioblastoma cell lines. We showed that gartisertib alone potently reduced the cell viability of glioblastoma cell lines, where sensitivity was associated with the frequency of DDR mutations and higher expression of the G2 cell cycle pathway. ATR inhibition significantly enhanced cell death in combination with TMZ and RT and was shown to have higher synergy than TMZ+RT treatment. MGMT promoter unmethylated and TMZ+RT resistant glioblastoma cells were also more sensitive to gartisertib. Analysis of gene expression from gartisertib treated glioblastoma cells identified the upregulation of innate immune-related pathways. Overall, this study identifies ATR inhibition as a strategy to enhance the DNA-damaging ability of glioblastoma standard treatment, while providing preliminary evidence that ATR inhibition induces an innate immune gene signature that warrants further investigation.