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AURKA and PLK1 inhibition selectively and synergistically block cell cycle progression in diffuse midline glioma
Dennis S Metselaar1,2, Aimée du Chatinier1, Michaël H Meel1
1Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584CS Utrecht, the Netherlands.
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.
Insights
Targeting Aurora kinase A (AURKA) and polo-like kinase 1 (PLK1) shows promise for treating diffuse midline gliomas (DMG). Inhibiting both kinases halts cancer cell division and repair, leading to cell death in pediatric brain tumors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Diffuse midline gliomas (DMG) are aggressive pediatric brain tumors with limited treatment options.
- Aurora kinase A (AURKA) is frequently overexpressed in DMG, suggesting its potential as a therapeutic target.
Purpose of the Study:
- To investigate AURKA as a therapeutic target in DMG.
- To identify synergistic targets with AURKA using CRISPR/Cas9 screening.
- To evaluate the efficacy of combined AURKA and polo-like kinase 1 (PLK1) inhibition in DMG models.
Main Methods:
- Overexpression analysis of AURKA in DMG.
- CRISPR/Cas9 screening to identify synergistic targets with AURKA inhibition.
- Treatment of patient-derived DMG cell cultures with AURKA and PLK1 inhibitors (volasertib).
- Cell cycle analysis and apoptosis assays.
Main Results:
- AURKA is overexpressed in DMG, validating it as a therapeutic target.
- CRISPR/Cas9 screening identified PLK1 as a synergistic target with AURKA.
- Combined inhibition of AURKA and PLK1 with volasertib induced G2/M cell cycle arrest.
- Dual inhibition blocked DNA-damage repair and promoted apoptosis specifically in DMG cells.
Conclusions:
- Concurrent targeting of AURKA and PLK1 represents a promising therapeutic strategy for diffuse midline gliomas.
- This dual-inhibition approach effectively halts DMG cell proliferation and induces apoptosis.
- Further investigation into this combination therapy is warranted for pediatric brain tumor treatment.
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