AURKA and PLK1 inhibition selectively and synergistically block cell cycle progression in diffuse midline glioma

iScience

Aimée du Chatinier¹  Gertjan J.L. Kaspers²  Jan Koster³  Marianna Bugiani⁴  Piotr Waranecki⁴  Michaël H. Meel⁵  Joshua R. Goulding⁵  Esther Hulleman⁵  Dennis S. Metselaar⁵  Giovanna ter Huizen⁵ 

[1] Emma Children’s Hospital, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Pediatric Oncology, Cancer Center Amsterdam, Amsterdam, the Netherlands;Department of Oncogenomics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands;Department of Pathology, Amstrdam University Medical Centers, Amsterdam, the Netherlands;Emma Children’s Hospital, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Pediatric Oncology, Cancer Center Amsterdam, Amsterdam, the Netherlands;Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584CS Utrecht, the Netherlands;

关键词: Biological sciences;    Cancer;    Cell biology;    Molecular biology;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary: Diffuse midline gliomas (DMG) are highly malignant incurable pediatric brain tumors. In this study, we show that Aurora kinase A (AURKA) is overexpressed in DMG and can be used as a therapeutic target. Additionally, AURKA inhibition combined with CRISPR/Cas9 screening in DMG cells, revealed polo-like kinase 1 (PLK1) as a synergistic target with AURKA. Using a panel of patient-derived DMG culture models, we demonstrate that treatment with volasertib, a clinically relevant and selective PLK1 inhibitor, synergizes with different AURKA inhibitors, supporting the CRISPR screen results. Mechanistically, our results show that combined loss of PLK1 and AURKA causes a G2/M cell cycle arrest which blocks vital parts of DNA-damage repair and induces apoptosis, solely in DMG cells. Altogether, our findings highlight the importance of AURKA and PLK1 for DMG propagation and demonstrate the potential of concurrently targeting these proteins as a therapeutic strategy for these devastating pediatric brain tumors.

【 授权许可】

Unknown