A series of work from Brian Hemmings groups has identified DNA-PKcs, as a central node, amplifies and conveys signals from the damaged DNA to DSBs repair and anti-apoptosis machineries, for example through AKT pathway, thus promoting survival [56, 57]. However, role of activated DNA-PKcs/AKT axis without chemo- or radiotherapy triggered has been completely ignored, which is certainly existed as our result illustrated. In fact, mountains of researches have observed that DNA-PKcs promotes tumor malignancies through stimulating and integrating an extensive network of cellular signaling which is not involving DNA damage repair [20, 23, 46]. Actually, in vitro assay has demonstrated that synthetic peptides of DNA-PKcs can phosphorylate AKT on Ser 473 , which provided a fundament that activated DNA-PKcs, whatever DSBs induced or non-DSBs induced, could potentially play an additional role in enhanced AKT signaling. This was confirmed by our clinical investigation that a linear correlation between p-DNA-PKcs and p-AKT expression was discovered. Such a finding shed light on the overlooked function of non-DSBs stimulated DNA-PKcs/AKT signal, which potentially promotes glioma progression.