Biology subjects

Bowden, N. A.

Publications and source records attributed to Bowden, N. A..

2 recordsLinked to original sources

bioRxiv2024

Upregulated cholesterol biosynthesis facilitates the survival of methylation-retaining AML cells following decitabine treatment.

DNA hypomethylating agents (HMAs) are used to treat acute myeloid leukemia (AML) and myelodysplasia patients who are unsuitable for intensive chemotherapy. However, low response rates and therapy-resistant relapse remain significant challenges. To improve outcomes, we must understand how AML cells survive HMA treatment and continue to proliferate following therapy. We combine single-cell multiomics with parallel colony-forming assays to link HMA-induced heterogeneity with functional consequences in AML cellss. Azacytidine (AZA) and decitabine (DAC) induced global epigenetic heterogeneity, associated with upregulation of inflammatory responses and cell death pathways in a subset of hypomethylated cells. Some cells maintained high DNA methylation levels during treatment, and these methylation-retaining cells had increased self-renewal capacity following DAC treatment in two FLT3-ITD AML cell lines. Transcriptional profiling of colonies formed after HMA treatment revealed many genes with altered expression in both methylation-retaining and hypomethylated cells, with increased expression of cholesterol-related genes observed in all cell lines. Inhibition of the cholesterol biosynthesis pathway by rosuvastatin enhanced HMA effects on colony formation in vitro and extended survival in two in vivo models of AML. Our study demonstrates that HMA-induced epigenetic heterogeneity has implications for AML cell growth and identifies statins as a candidate co-treatment strategy to improve HMA efficacy.

cancer biology↗

bioRxiv2023

ATR inhibition using gartisertib enhances cell death and synergises with temozolomide and radiation in patient-derived glioblastoma cell lines

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.

cancer biology↗