Combinatorial Effect of PLK1 Inhibition with Temozolomide and Radiation in Glioblastoma

Simple Summary: There is a critical need to identify readily translatable adjuncts to potentiate the dismal median survivals of only 15-20 months in glioblastoma (GBM) patients after standard of care, i.e., concurrent Temozolomide (TMZ) and radiation (XRT) therapy. Here we demonstrated that the Polo-like kinase 1 (PLK1) inhibitor volasertib, which has been employed in cancer clinical trials, has activity against GBM in the contexts of both as monotherapy and as an adjunct to standard of care (SOC). In addition to corroborating the known effects of volasertib, we found novel impacts of volasertib on mitochondrial membrane potential, ROS generation, persistent DNA damage and signaling pathways such as ERK/MAPK, AMPK and glucocorticoid receptor. Together these studies support the potential importance of PLK1 inhibitors as an adjunct to GBM SOC therapy that warrants further preclinical investigation.New strategies that improve median survivals of only ~15-20 months for glioblastoma (GBM) with the current standard of care (SOC) which is concurrent temozolomide (TMZ) and radiation (XRT) treatment are urgently needed. Inhibition of polo-like kinase 1 (PLK1), a multifunctional cell cycle regulator, overexpressed in GBM has shown therapeutic promise but has never been tested in the context of SOC. Therefore, we examined the mechanistic and therapeutic impact of PLK1 specific inhibitor (volasertib) alone and in combination with TMZ and/or XRT on GBM cells. We quantified the effects of volasertib alone and in combination with TMZ and/or XRT on GBM cell cytotoxicity/apoptosis, mitochondrial membrane potential (MtMP), reactive oxygen species (ROS), cell cycle, stemness, DNA damage, DNA repair genes, cellular signaling and in-vivo tumor growth. Volasertib alone and in combination with TMZ and/or XRT promoted apoptotic cell death, altered MtMP, increased ROS and G2/M cell cycle arrest. Combined volasertib and TMZ treatment reduced side population (SP) indicating activity against GBM stem-like cells. Volasertib combinatorial treatment also significantly increased DNA damage and reduced cell survival by inhibition of DNA repair gene expression and modulation of ERK/MAPK, AMPK and glucocorticoid receptor signaling. Finally, as observed in-vitro, combined volasertib and TMZ treatment resulted in synergistic inhibition of tumor growth in-vivo. Together these results identify new mechanisms of action for volasertib that provide a strong rationale for further investigation of PLK1 inhibition as an adjunct to current GBM SOC therapy.