MAPK inhibitor sensitivity scores predict sensitivity driven by the immune infiltration in pediatric low-grade gliomas
Pediatric low-grade gliomas (pLGG) show heterogeneous responses to MAPK inhibitors (MAPKi) in clinical trials. Thus, more complex stratification biomarkers are needed to identify patients likely to benefit from MAPKi therapy. Here, we identify MAPK-related genes enriched in MAPKi-sensitive cell line...
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| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
27 July 2023
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| In: |
Nature Communications
Year: 2023, Jahrgang: 14, Pages: 1-21 |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-023-40235-8 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-023-40235-8 Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-023-40235-8 
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| Verfasserangaben: | Romain Sigaud, Thomas K. Albert, Caroline Hess, Thomas Hielscher, Nadine Winkler, Daniela Kocher, Carolin Walter, Daniel Münter, Florian Selt, Diren Usta, Jonas Ecker, Angela Brentrup, Martin Hasselblatt, Christian Thomas, Julian Varghese, David Capper, Ulrich W. Thomale, Pablo Hernáiz Driever, Michèle Simon, Svea Horn, Nina Annika Herz, Arend Koch, Felix Sahm, Stefan Hamelmann, Augusto Faria-Andrade, Nada Jabado, Martin U. Schuhmann, Antoinette Y. N. Schouten-van Meeteren, Eelco Hoving, Tilman Brummer, Cornelis M. van Tilburg, Stefan M. Pfister, Olaf Witt, David T. W. Jones, Kornelius Kerl & Till Milde |
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| 245 | 1 | 0 | |a MAPK inhibitor sensitivity scores predict sensitivity driven by the immune infiltration in pediatric low-grade gliomas |c Romain Sigaud, Thomas K. Albert, Caroline Hess, Thomas Hielscher, Nadine Winkler, Daniela Kocher, Carolin Walter, Daniel Münter, Florian Selt, Diren Usta, Jonas Ecker, Angela Brentrup, Martin Hasselblatt, Christian Thomas, Julian Varghese, David Capper, Ulrich W. Thomale, Pablo Hernáiz Driever, Michèle Simon, Svea Horn, Nina Annika Herz, Arend Koch, Felix Sahm, Stefan Hamelmann, Augusto Faria-Andrade, Nada Jabado, Martin U. Schuhmann, Antoinette Y. N. Schouten-van Meeteren, Eelco Hoving, Tilman Brummer, Cornelis M. van Tilburg, Stefan M. Pfister, Olaf Witt, David T. W. Jones, Kornelius Kerl & Till Milde |
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| 520 | |a Pediatric low-grade gliomas (pLGG) show heterogeneous responses to MAPK inhibitors (MAPKi) in clinical trials. Thus, more complex stratification biomarkers are needed to identify patients likely to benefit from MAPKi therapy. Here, we identify MAPK-related genes enriched in MAPKi-sensitive cell lines using the GDSC dataset and apply them to calculate class-specific MAPKi sensitivity scores (MSSs) via single-sample gene set enrichment analysis. The MSSs discriminate MAPKi-sensitive and non-sensitive cells in the GDSC dataset and significantly correlate with response to MAPKi in an independent PDX dataset. The MSSs discern gliomas with varying MAPK alterations and are higher in pLGG compared to other pediatric CNS tumors. Heterogenous MSSs within pLGGs with the same MAPK alteration identify proportions of potentially sensitive patients. The MEKi MSS predicts treatment response in a small set of pLGG patients treated with trametinib. High MSSs correlate with a higher immune cell infiltration, with high expression in the microglia compartment in single-cell RNA sequencing data, while low MSSs correlate with low immune infiltration and increased neuronal score. The MSSs represent predictive tools for the stratification of pLGG patients and should be prospectively validated in clinical trials. Our data supports a role for microglia in the response to MAPKi. | ||
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