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, Michaël 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 - Funding Information: The authors would like to acknowledge Madelaine van Mackelenbergh, from the Princess Maxima Center (Utrecht, Netherlands), for her assistance with figure preparation and graphic design. Funding was provided by the Children Cancer Free Foundation (KIKA, Netherlands), within project number 210. D.S.M. and E.H. conceived and designed the project. D.S.M. A.D.C. M.H.M. and P.Wa. developed and validated the in vitro models used in the study. D.S.M. A.D.C. J.R.G. and P.Wa. performed the functional in vitro and western blotting.experiments. D.S.M. and M.B. provided patient-derived DMG tissues and performed immunohistochemical stainings. D.S.M. J.R.G. and P.Wa optimized and performed the CRISPR/Cas9 experiments. D.S.M. and A.D.C. performed in silico data analysis J.K. provided bioinformatical and statistical expertise and support. G.J.L.K. and E.H. acquired funding and supervised the study. All authors contributed to writing the manuscript. The authors have no conflicts of interest to declare. Funding Information: The authors would like to acknowledge Madelaine van Mackelenbergh, from the Princess Maxima Center (Utrecht, Netherlands), for her assistance with figure preparation and graphic design. Funding was provided by the Children Cancer Free Foundation (KIKA, Netherlands), within project number 210 . Publisher Copyright: © 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.
KW - Biological sciences
KW - Cancer
KW - Cell biology
KW - Molecular biology
UR - http://www.scopus.com/inward/record.url?scp=85131085512&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.isci.2022.104398
DO - https://doi.org/10.1016/j.isci.2022.104398
M3 - Article
C2 - 35637734
SN - 2589-0042
VL - 25
JO - iScience
JF - iScience
IS - 6
M1 - 104398
ER -