Abstract
Glioblastoma multiforme (GBM) is the most aggressive human primary brain cancer. Using a Trp53-deficient mouse model of GBM, we show that genetic inactivation of the Atm cofactor Atmin, which is dispensable for embryonic and adult neural development, strongly suppresses GBM formation. Mechanistically, expression of several GBM-associated genes, including Pdgfra, was normalized by Atmin deletion in the Trp53-null background. Pharmacological ATM inhibition also reduced Pdgfra expression, and reduced the proliferation of Trp53-deficient primary glioma cells from murine and human tumors, while normal neural stem cells were unaffected. Analysis of GBM datasets showed that PDGFRA expression is also significantly increased in human TP53-mutant compared with TP53-wild-type tumors. Moreover, combined treatment with ATM and PDGFRA inhibitors efficiently killed TP53-mutant primary human GBM cells, but not untransformed neural stem cells. These results reveal a new requirement for ATMIN-dependent ATM signaling in TP53-deficient GBM, indicating a pro-tumorigenic role for ATM in the context of these tumors.
Highlights
Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain cancer in adults
Loss of Atmin impairs the tumorigenicity of neural stem cells in orthotopic transplants As increased proliferation and hypoxia resistance are attributes commonly found in tumor initiating cells of solid tumors, including glioma (Graeber et al, 1996; Gilbertson and Rich, 2007), we evaluated the tumorigenic potential of p53DN and AtminDN; p53DN NSCs in vivo
Since Atm is best known as a DNA damage signaling kinase, we examined whether the effect of Atm on platelet-derived growth factor receptor alpha (Pdgfra) expression and tumorigenicity was related to altered DNA damage signaling in p53DNglioma cells
Summary
Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain cancer in adults. Blake et al studied primary human glioblastoma cells that lack TP53 and found that these cells could be efficiently killed by a combination of drugs that block the activity of PDGFRA and the protein ATM, which is known to work in concert with ATMIN. This combination of drugs did not adversely affect healthy brain cells, opening up new strategies and potential treatment options for glioblastoma patients. We find that these results are translatable to therapeutic ATM inhibition in human patient-derived GBM stem cells, and that combining ATM inhibition with PDGFRA inhibition results in synergistic tumor cell killing with minimal effects on untransformed cells
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