Repression of Aurora kinase B prevents growth and tissue invasion in medulloblastoma

Abstract

Novel treatment strategies are required to overcome therapy-associated sequelae in survivors of pediatric medulloblastoma (MB) while maintaining therapeutic efficacy. The tissue impact on drug response in MB is not well understood and drug profiling in the physiological context of the tissue may reveal novel therapy targets. To gain insights into the growth and dissemination behavior of the MB tumor cells under treatment, we combined three-dimensional cell culture screening with ex vivo organotypic cerebellum slice co-culture (OCSC), which allowed assessing tumor cell behavior in the tissue context. We screened a panel of 274 kinase inhibitors and identified aurora kinase B (AURKB) as a potential anti-invasion drug target in MB. We validated tumor suppressive activities of the AURKB inhibitor (AURKBi) barasertib and the structurally unrelated compound GSK-1070916 in cerebellum slice culture models for SHH, Grp3 and Grp4 MB at nanomolar concentrations. We confirmed the necessity of AURKB for tumor growth through genetic suppression of AURKB by siRNA in the tissue context. We revealed that the combination of AURKBi with the SRC/BCR-ABL inhibitor dasatinib acts synergistically to repress tumor growth and invasiveness in the SHH MB cell model ONS76, but not in Grp3 MB cells. Finally, we demonstrate that pharmacological repression of AURKB in the tissue context is as effective as X-ray irradiation to repress tumor growth. Our data highlight that AURKBi is equally efficient as irradiation, suggesting that pharmacological targeting of AURKB may constitute a novel means to overcome radiotherapy limitations in patients younger than three years. Importance of the studyOur data demonstrate anti-tumor activity of AURKB inhibitors in the tissue context for MB tumor cells that are in vitro resistant to the treatment. This indication of a tissue component to drug response contributes critical insights for drug response profiling for brain tumors. AURKB inhibitors barasertib and GSK-1070916 block growth and invasiveness of SHH, Grp3 and Grp4 MB tumor cells as well as primary ATRT. Importantly, AURKBi is equally efficient as irradiation. In conclusion, a tissue component contributes to sensitivity to AURKB inhibition and pharmacological targeting of AURKB may constitute a novel means to overcome radiotherapy limitations in patients younger than three years. Key pointsO_LIAURKB is essential for in tissue growth of MB. C_LIO_LIInactivation of AURKB causes p53 upregulation and decreased in tissue growth and dissemination. C_LIO_LIAURKB inhibition in the tissue context is as effective as irradiation to restrict tumor cell growth. C_LI