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

Dennis S. Metselaar, Aimée du Chatinier, Michael H. Meel, Giovanna ter Huizen, Piotr Waranecki, Joshua R. Goulding, Marianna Bugiani, Jan Koster, Gertjan J.L. Kaspers, Esther Hulleman

Research output: Contribution to journalArticlepeer-review

Abstract

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.
Original languageEnglish
JournaliScience
Volume25
Issue number6
DOIs
Publication statusPublished - 13 May 2022

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