Dual PI3K/mTOR Inhibitor, XL765, suppresses glioblastoma growth by inducing ER stress-dependent apoptosis

Background: Deregulated phosphoinositide 3-kinase (PI3K)/mTOR signaling commonly exists in glioblastoma (GBM), making this axis an attractive target for therapeutic manipulation. A recent dual inhibitor of PI3K/mTOR pathway, XL765, exhibited an attractive suppression effect on GBM tumor growth. However, the exact functional mechanisms of tumor suppression mediated by XL765 have not yet been fully characterized. Purpose: In this study, we took efforts to assess the effects of PI3K/mTOR blockade by XL765 on GBM growth in vitro and in vivo. Methods: We analyzed the cytotoxicity of XL765 in three different GBM cell lines, A172, U87MG, and T98G, by using Hoechst 33258 (Invitrogen), Annexin V/propidium iodide (PI), as well as Cell Counting Kit -8 (CCK‐8) assay. We also used A172 xenograft model to study the effect of XL765 in vivo. Results: We found that XL765 inhibits GBM viability with a wide range of potencies. Importantly, XL765 suppressed GBM cell growth by inducing endoplasmic reticulum (ER) stress dependent apoptosis. The activation of CHOP/DR5 pathway by XL765 induced ER stress is responsible for the induction of apoptosis. Moreover, the inhibition of mTOR signal by XL765 is the major source of ER stress, rather than inhibition of PI3K. At last, we demonstrated that combination of XL765 with GMB chemotherapeutic drug, temozolomide (TMZ), can achieved better therapy effect in vitro and in vivo. Conclusion: Overall, our data show that targeting PI3K/mTOR by XL765 is a promising therapeutic strategy to relieve tumor burden in GBM patients.