Abstract 4811: Inhibition of PLK1 abrogates side population and increases radiation-induced DNA damage in human glioblastoma

Abstract

Abstract Glioblastoma multiforme (GBM), a highly malignant form of brain tumor has limited treatment modalities with poor patient survival. Expression of CD133, a marker of cancer stem cells (CSCs), has been linked to GBM recurrence, metastasis and radiation/drug resistance. The GBM CSCs exhibit high level of ABC transporters, DNA repair enzymes and anti-apoptotic proteins. The side population (SP) phenotype of CSCs with high levels of ABC transporters is associated with chemo-resistance. Overexpression of Polo-like kinase-1 (PLK1), a key cell cycle regulator, has been linked to poor prognosis of various cancers. However, the role of PLK1 in radio/chemo-resistance of GBM is poorly understood. In this study, we explored the use of PLK1 inhibitor Volasertib in combination with temozolomide (TMZ) followed by radiation to overcome resistance in GBM, both in vitro and in vivo. Our results revealed that Volasertib and TMZ act synergistically at a sub-lethal dose to inhibit cell proliferation and induce apoptosis. Both Volasertib and TMZ strongly induce reactive oxygen species (ROS) which may cause cell death by reducing repair capacity. Combined treatment with TMZ and Volasertib followed by radiation showed persistent DNA damage after removal of drugs for 24 hrs. In contrast to earlier reports, significant decrease in the side population was also observed, even after radiation treatment. We also observed that Volasertib alone or in combination with TMZ activated STAT1 pathways and inhibited MAPK/AKT activation. As the latter pathway promotes apoptosis, our results suggest higher tumor growth inhibitory effect of combinatorial treatment compared to single agents in xenograft mouse model. In summary, while Volasertib can be used alone or in the combination with radiation, Volasertib combined with TMZ may be useful to inhibit recurrence of GBM after radiation therapy. Furthermore, increased STAT1 expression may modulate the tumor-microenvironment and improve immunotherapy by MHC class 1 upregulation. Citation Format: Arvind Pandey, Junhua Mai, Satyendra C. Tripathi, Samir M. Hanash, Haifa Shen, Sankar Mitra. Inhibition of PLK1 abrogates side population and increases radiation-induced DNA damage in human glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4811.