Journal Article

MAPK inhibitor sensitivity scores predict sensitivity driven by the immune infiltration in pediatric low-grade gliomas

Faria-Andrade, Augusto, Usta, Diren, Sahm, Felix, Winkler, Nadine, Witt, Olaf, Herz, Nina Annika, Schuhmann, Martin U., Brentrup, Angela, Münter, Daniel, Hamelmann, Stefan, Thomas, Christian, Schouten-van Meeteren, Antoinette Y. N., Sigaud, Romain, Hernáiz Driever, Pablo, Jones, David T. W., Kerl, Kornelius, Hoving, Eelco, Pfister, Stefan M., Hasselblatt, Martin, Milde, Till, Simon, Michèle, Hess, Caroline, Koch, Arend, Horn, Svea, Selt, Florian, Hielscher, Thomas, Ecker, Jonas, Brummer, Tilman, Thomale, Ulrich W., van Tilburg, Cornelis M., Albert, Thomas K., Kocher, Daniela, Jabado, Nada, Walter, Carolin, Capper, David, Varghese, Julian

2023

Overview

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. The MAPK pathway is a key driver of pediatric low-grade gliomas (pLGG); however, response to MAPK inhibitors (MAPKi) in pLGG patients is not consistent. Here, the authors develop MAPKi sensitivity scores (MSS) to predict response to MAPKi and apply them to bulk and single-cell sequencing datasets from pLGG patients and preclinical models.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/95 / 38/91 / 42/44 / 631/154/53/2423 / 631/67/1922 / 631/67/2332 / 631/67/327 / 631/67/69 / Biomarkers / Brain tumors / Cell Line / Cell lines / Child / Clinical trials / Datasets / Gene sequencing / Gene set enrichment analysis / Glioma / Glioma - drug therapy / Glioma - genetics / Glioma - metabolism / Humanities and Social Sciences / Humans / Immune system / Infiltration / Inhibitor drugs / Inhibitors / MAP kinase / Metastases / Microglia / multidisciplinary / Patients / Pediatrics / Protein Kinase Inhibitors - pharmacology / Protein Kinase Inhibitors - therapeutic use / Science / Science (multidisciplinary)