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Rebound growth of BRAF mutant pediatric glioma cells after MAPKi withdrawal is associated with MAPK reactivation and secretion of microglia-recruiting cytokines

INTRODUCTION: Patients with pediatric low-grade gliomas (pLGGs), the most common primary brain tumors in children, can often benefit from MAPK inhibitor (MAPKi) treatment. However, rapid tumor regrowth, also referred to as rebound growth, may occur once treatment is stopped, constituting a significa...

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Main Authors: Kocher, Daniela (Author) , Cao, Lei (Author) , Guiho, Romain (Author) , Langhammer, Melanie (Author) , Lai, Yun-Lu (Author) , Becker, Pauline (Author) , Hamdi, Hiba (Author) , Friedel, Dennis (Author) , Selt, Florian (Author) , Vonhören, David (Author) , Zaman, Julia (Author) , Valinciute, Gintvile (Author) , Herter, Sonja (Author) , Picard, Daniel (Author) , Rettenmeier, Johanna (Author) , Maaß, Kendra K. (Author) , Pajtler, Kristian Wilfried (Author) , Remke, Marc (Author) , Deimling, Andreas von (Author) , Pusch, Stefan (Author) , Pfister, Stefan (Author) , Oehme, Ina (Author) , Jones, David T. W. (Author) , Halbach, Sebastian (Author) , Brummer, Tilman (Author) , Martinez-Barbera, Juan Pedro (Author) , Witt, Olaf (Author) , Milde, Till (Author) , Sigaud, Romain (Author)
Format: Article (Journal)
Language:English
Published: 17 April 2024
In: Journal of neuro-oncology
Year: 2024, Volume: 168, Issue: 2, Pages: 317-332
ISSN:1573-7373
DOI:10.1007/s11060-024-04672-9
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1007/s11060-024-04672-9
Resolving-System, kostenfrei, Volltext: https://link.springer.com/article/10.1007/s11060-024-04672-9
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Author Notes:Daniela Kocher, Lei Cao, Romain Guiho, Melanie Langhammer, Yun-Lu Lai, Pauline Becker, Hiba Hamdi, Dennis Friedel, Florian Selt, David Vonhören, Julia Zaman, Gintvile Valinciute, Sonja Herter, Daniel Picard, Johanna Rettenmeier, Kendra K. Maass, Kristian W. Pajtler, Marc Remke, Andreas von Deimling, Stefan Pusch, Stefan M. Pfister, Ina Oehme, David T.W. Jones, Sebastian Halbach, Tilman Brummer, Juan Pedro Martinez-Barbera, Olaf Witt, Till Milde, Romain Sigaud
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Summary:INTRODUCTION: Patients with pediatric low-grade gliomas (pLGGs), the most common primary brain tumors in children, can often benefit from MAPK inhibitor (MAPKi) treatment. However, rapid tumor regrowth, also referred to as rebound growth, may occur once treatment is stopped, constituting a significant clinical challenge. - METHODS: Four patient-derived pediatric glioma models were investigated to model rebound growth in vitro based on viable cell counts in response to MAPKi treatment and withdrawal. A multi-omics dataset (RNA sequencing and LC-MS/MS based phospho-/proteomics) was generated to investigate possible rebound-driving mechanisms. Following in vitro validation, putative rebound-driving mechanisms were validated in vivo using the BT-40 orthotopic xenograft model. - RESULTS: Of the tested models, only a BRAFV600E-driven model (BT-40, with additional CDKN2A/Bdel) showed rebound growth upon MAPKi withdrawal. Using this model, we identified a rapid reactivation of the MAPK pathway upon MAPKi withdrawal in vitro, also confirmed in vivo. Furthermore, transient overactivation of key MAPK molecules at transcriptional (e.g. FOS) and phosphorylation (e.g. pMEK) levels, was observed in vitro. Additionally, we detected increased expression and secretion of cytokines (CCL2, CX3CL1, CXCL10 and CCL7) upon MAPKi treatment, maintained during early withdrawal. While increased cytokine expression did not have tumor cell intrinsic effects, presence of these cytokines in conditioned media led to increased attraction of microglia cells in vitro. - CONCLUSION: Taken together, these data indicate rapid MAPK reactivation upon MAPKi withdrawal as a tumor cell intrinsic rebound-driving mechanism. Furthermore, increased secretion of microglia-recruiting cytokines may play a role in treatment response and rebound growth upon withdrawal, warranting further evaluation.
Item Description:Gesehen am 28.03.2025
Physical Description:Online Resource
ISSN:1573-7373
DOI:10.1007/s11060-024-04672-9

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