TY - JOUR
T1 - AURKA and PLK1 inhibition selectively and synergistically block cell cycle progression in diffuse midline glioma
AU - Metselaar, Dennis S.
AU - du Chatinier, Aimée
AU - Meel, Michael H.
AU - ter Huizen, Giovanna
AU - Waranecki, Piotr
AU - Goulding, Joshua R.
AU - Bugiani, Marianna
AU - Koster, Jan
AU - Kaspers, Gertjan J.L.
AU - Hulleman, Esther
N1 - © 2022 The Author(s).
PY - 2022/6/17
Y1 - 2022/6/17
N2 - 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.
AB - 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.
U2 - 10.1016/j.isci.2022.104398
DO - 10.1016/j.isci.2022.104398
M3 - Article
C2 - 35637734
SN - 2589-0042
VL - 25
SP - 104398
JO - iScience
JF - iScience
IS - 6
ER -