TY  - JOUR
AU  - Xing, Yao Lulu
AU  - Panovska, Dena
AU  - Park, Jong-Whi
AU  - Grossauer, Stefan
AU  - Koeck, Katharina
AU  - Bui, Brandon
AU  - Nasajpour, Emon
AU  - Nirschl, Jeffrey J
AU  - Feng, Zhi-Ping
AU  - Cheung, Pierre
AU  - Habib, Pardes
AU  - Wei, Ruolun
AU  - Wang, Jie
AU  - Thomason, Wes
AU  - Monje, Michelle
AU  - Xiu, Joanne
AU  - Beck, Alexander
AU  - Weber, Katharina
AU  - Harter, Patrick N
AU  - Lim, Michael
AU  - Mahaney, Kelly B
AU  - Prolo, Laura M
AU  - Grant, Gerald A
AU  - Ji, Xuhuai
AU  - Walsh, Kyle M
AU  - Mulcahy Levy, Jean M
AU  - Hambardzumyan, Dolores
AU  - Petritsch, Claudia K
TI  - BRAF/MEK inhibition induces cell state transitions boosting immune checkpoint sensitivity in BRAFV600E-mutant glioma.
JO  - Cell reports / Medicine
VL  - 6
IS  - 6
SN  - 2666-3791
CY  - Cambridge, MA
PB  - Cell Press
M1  - DKFZ-2025-01212
SP  - 102183
PY  - 2025
N1  - 2025 Jun 17;6(6):102183
AB  - 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.
KW  - BRAF V600E (Other)
KW  - BRAF and MEK inhibitor adaptation (Other)
KW  - Galectin-3 (Other)
KW  - T cell modulation (Other)
KW  - cell state transitions (Other)
KW  - high-grade glioma (Other)
KW  - immune checkpoint inhibition (Other)
KW  - programmed death-ligand 1 (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:40505659
DO  - DOI:10.1016/j.xcrm.2025.102183
UR  - https://inrepo02.dkfz.de/record/302014
ER  -