Is inhibiting the DNA damage response the answer to treatment resistance in glioma stem cells?

Abstract

: Research efforts in the last decade have increased our understanding of the complexity and treatment resistance of aggressive stage IV gliomas (GBMs) that result in a dismal prognosis for GBM patients. GBMs have inherent plasticity; a single tumor consists of many phenotypes, including glioma stem-like cells (GSCs) that have the ability to recreate all tumor phenotypes. GSCs are particularly resistant to treatment, upregulating various growth factor receptor signaling pathways as well as the DNA damage response pathway and switching metabolic phenotypes when necessary. A whole raft of monoclonal antibodies and small molecule tyrosine kinase inhibitors targeting growth factor receptor pathways have shown promise in preclinical studies but have failed in clinical trials. More recently, inhibitors of the DNA damage response pathway, resulting in cell cycle checkpoint blockade, have demonstrated strong radiosensitizing effects, particularly in GSCs with mutated p53. This perspective covers the different mechanisms that underlie GSC treatment resistance and recaps our current understanding of the radiosensitizing effects of ATM inhibitors on GBMs and GSCs in particular.