EXTH-43. XPO1 INHIBITOR SELINEXOR SENSITIVITY IN GLIOBLASTOMA: POTENTIAL ROLE OF MGMT ACTIVATION THROUGH PKA-CREB PATHWAY

Abstract

Abstract INTRODUCTION Glioblastoma (GBM) is the most common and aggressive form of adult brain tumor and is an incurable disease due to primary and secondary resistance to therapy. We recently examined the candidate genes modulating temozolomide (TMZ) resistance using genome-wide shRNA screening in TMZ-resistant U251 (U251TMZ) model. We identified a total of 134 TMZ-resistant candidate genes, including Karyopherin A1 (KPNA1) and Exportin 1 (XPO1), the genes critical for nucleocytoplasmic (NC)-transport. Interestingly, XPO1 inhibitor Selinexor is an FDA-approved agent for refractory multiple myeloma, and there is an ongoing interest in evaluating Selinexor for GBM therapy. Therefore, we hypothesized that Selinexor is a promising drug for overcoming TMZ resistance. METHODS and RESULTS We conducted a series of experiments in vitro using Selinexor with and without TMZ. Selinexor and TMZ alone didn’t significantly block the growth of U251TMZ cells. In contrast, Selinexor significantly re-sensitized resistant U251TMZ cells to TMZ. Interestingly, MGMT-methylated GBM39 cells were sensitive to Selinexor alone, TMZ alone, and to combined Selinexor/TMZ treatment. Contrarily, MGMT-unmethylated GBM43 cells were only sensitive to combined Selinexor/TMZ treatment. These findings suggested that similar to TMZ, Selinexor sensitivity may be influenced by MGMT expression status, with MGMT expressing cells showing resistance. In line with this notion, re-expression of exogeneous MGMT blocked sensitivity of MGMT-methylated U251 cells to Selinexor and TMZ, but such inhibition was not observed in U251 expressing vector alone. Interestingly, the concentration-dependent experiments demonstrated that Selinexor can induce MGMT expression in unmethylated T98G, GBM6, GBM14, and GBM43 cells. Selinexor-induced MGMT expression was accompanied with increased phosphorylation of CREB protein. CONCLUSION These results suggest that Selinexor sensitivity alone and with TMZ may be limited to MGMT-methylated GBM cells and may increase MGMT expression in unmethylated cells through activation of PKA-CREB pathway. Future studies will evaluate how MGMT may impact the sensitivity of GBM cells to Selinexor.