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@ARTICLE{Xing:302014,
author = {Y. L. Xing and D. Panovska and J.-W. Park and S. Grossauer
and K. Koeck and B. Bui and E. Nasajpour and J. J. Nirschl
and Z.-P. Feng and P. Cheung and P. Habib and R. Wei and J.
Wang and W. Thomason and M. Monje and J. Xiu and A. Beck and
K. Weber$^*$ and P. N. Harter and M. Lim and K. B. Mahaney
and L. M. Prolo and G. A. Grant and X. Ji and K. M. Walsh
and J. M. Mulcahy Levy and D. Hambardzumyan and C. K.
Petritsch},
title = {{BRAF}/{MEK} inhibition induces cell state transitions
boosting immune checkpoint sensitivity in
{BRAFV}600{E}-mutant glioma.},
journal = {Cell reports / Medicine},
volume = {6},
number = {6},
issn = {2666-3791},
address = {Cambridge, MA},
publisher = {Cell Press},
reportid = {DKFZ-2025-01212},
pages = {102183},
year = {2025},
note = {2025 Jun 17;6(6):102183},
abstract = {Resistance to v-raf murine sarcoma viral oncogene homolog
B1 (BRAF) plus mitogen-activated protein kinase kinase (MEK)
inhibition (BRAFi+MEKi) in BRAFV600E-mutant gliomas drives
rebound, progression, and high mortality, yet it remains
poorly understood. This study addresses the urgent need to
develop treatments for BRAFi+MEKi-resistant glioma using
preclinical mouse models and patient-derived materials.
BRAFi+MEKi reveals glioma plasticity by heightening cell
state transitions along glial differentiation trajectories,
giving rise to astrocyte- and immunomodulatory
oligodendrocyte (OL)-like states. PD-L1 upregulation in
OL-like cells links cell state transitions to immune
evasion, possibly orchestrated by Galectin-3. BRAFi+MEKi
induces interferon response signatures, tumor infiltration,
and suppression of T cells. Combining BRAFi+MEKi with immune
checkpoint inhibition enhances survival in a T
cell-dependent manner, reinvigorates T cells, and
outperforms individual or sequential therapies in mice.
Elevated PD-L1 expression in BRAF-mutant versus
BRAF-wild-type glioblastoma supports the rationale for PD-1
inhibition in patients. These findings underscore the
potential of targeting glioma plasticity and highlight
combination strategies to overcome therapy resistance in
BRAFV600E-mutant high-grade glioma.},
keywords = {BRAF V600E (Other) / BRAF and MEK inhibitor adaptation
(Other) / Galectin-3 (Other) / T cell modulation (Other) /
cell state transitions (Other) / high-grade glioma (Other) /
immune checkpoint inhibition (Other) / programmed
death-ligand 1 (Other)},
cin = {FM01},
ddc = {610},
cid = {I:(DE-He78)FM01-20160331},
pnm = {899 - ohne Topic (POF4-899)},
pid = {G:(DE-HGF)POF4-899},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:40505659},
doi = {10.1016/j.xcrm.2025.102183},
url = {https://inrepo02.dkfz.de/record/302014},
}