ATPS-20AURORA KINASE B INHIBITOR AT9283 ENHANCED RADIATION THERAPY IN GLIOBLASTOMA

Abstract

High-grade gliomas are the most common type of primary brain tumor in adults. Of the three main therapies, surgical resection, radiation therapy and chemotherapy, radiation remains the most important and relatively efficacious therapy for primary brain tumors. However, most patients are refractory to radiation therapy, and this radio resistance ultimately leads to tumor recurrence. Aurora kinase A, B and C, are key regulators of mitosis and are over expressed in many of the human cancers. Given that radiosensitization may be enhanced for cells at theG2/Mphase of the cell cycle, we attempted to increase radio sensitivity by treating cells with AT9283, a broad spectrum kinase inhibitor that potently inhibits Aurora A, Aurora B, JAK2, JAK3, and c-ABL. In this study, the in vitro therapeutic efficacy of AT9283 alone and in combination with radiation was investigated in a panel of gliomas stem cell (GSC) lines with specific molecular subtypes. Efficacy ofAT9283 was analyzed by Cell-Titer Glo 5 days after treatment. Molecular and cellular changes were approached by immunoblotting and flow cytometry. AT9283 inhibited cell viability with an IC50 ranging from 0.078 μM to 3.15 μM, suppressed phosphorylation of histone H3(Ser10) and phosphorylation of Aurora A/B/C in a dose- and time- dependent manner. AT-9283is effective in inducingG2/Marrestand polyploidy cell formation, which is a consequence of mitotic defects. Treatment withAT9283 induced prominent cleaved poly ADP ribose polymerase (PARP), an index of apoptosis. AT9283 suppressed colony formation and this effect was enhanced by combination therapy with radiation. The promising in vitro results of AT9283 in GSCs led to further investigation of drug efficacy in an intracranial xenograft models comparing AT9283 alone, and in combination with radiation. In summary, this study demonstrates that AT9283 is a novel therapeutic approach for the treatment of glioblastoma alone and in combination with radiation.