ATR Inhibition Using Gartisertib Enhances Cell Death and Synergises with Temozolomide and Radiation | Oncotarget

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January 16, 2024

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  • Oncotarget published this trending research #paper on January 16, 2024 in Volume 15, entitled, “ATR inhibition using gartisertib enhances cell death and synergises with temozolomide and radiation in patient-derived glioblastoma cell lines” by researchers from the School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, NSW, Australia; School of Medicine and Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, NSW, Australia; Drug Repurposing and Medicines Research Program, Hunter Medical Research Institute, New Lambton, NSW, Australia; Mark Hughes Foundation Centre for Brain Cancer Research, University of Newcastle, NSW, Australia; GenesisCare, Newcastle, NSW, Australia; QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD, Australia. DOI - https://doi.org/10.18632/oncotarget.28551 Correspondence to - Paul A. Tooney - paul.tooney@newcastle.edu.au 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. Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28551 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, glioblastoma, DNA damage response, ataxia-telangiectasia and rad3-related protein, radiation therapy, temozolomide About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

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