TY  - JOUR
AU  - Sigaud, Romain
AU  - Albert, Thomas K
AU  - Hess, Caroline
AU  - Hielscher, Thomas
AU  - Winkler, Nadine
AU  - Kocher, Daniela
AU  - Walter, Carolin
AU  - Münter, Daniel
AU  - Selt, Florian
AU  - Usta, Diren
AU  - Ecker, Jonas
AU  - Brentrup, Angela
AU  - Hasselblatt, Martin
AU  - Thomas, Christian
AU  - Varghese, Julian
AU  - Capper, David
AU  - Thomale, Ulrich W
AU  - Hernáiz Driever, Pablo
AU  - Simon, Michèle
AU  - Horn, Svea
AU  - Herz, Nina Annika
AU  - Koch, Arend
AU  - Sahm, Felix
AU  - Hamelmann, Stefan
AU  - Faria-Andrade, Augusto
AU  - Jabado, Nada
AU  - Schuhmann, Martin U
AU  - Schouten-van Meeteren, Antoinette Y N
AU  - Hoving, Eelco
AU  - Brummer, Tilman
AU  - van Tilburg, Cornelis Martinus
AU  - Pfister, Stefan M
AU  - Witt, Olaf
AU  - Jones, David
AU  - Kerl, Kornelius
AU  - Milde, Till
TI  - MAPK inhibitor sensitivity scores predict sensitivity driven by the immune infiltration in pediatric low-grade gliomas.
JO  - Nature Communications
VL  - 14
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DKFZ-2023-01521
SP  - 4533
PY  - 2023
N1  - #EA:B310#LA:B310#
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:37500667
DO  - DOI:10.1038/s41467-023-40235-8
UR  - https://inrepo02.dkfz.de/record/277810
ER  -