| HRA003740
(Controlled Access)
|
Diffuse intrinsic pontine gliomas (DIPG) are the most aggressive pediatric brainstem tumors. Currently, there is no cure for DIPG. Here, using drug screening of a set of epigenetic compounds with multiple patient-derived DIPG cells, we demonstrated that gemcitabine and fimepbinostat have anti-tumor efficacy in H3.3K27M DIPG. Firstly, we showed that gemcitabine treatment increased chromatin accessibility of p53 at apoptosis-related genes loci. Notably, the H3.3K27M mutation facilitates gemcitabine-induced apoptosis in DIPG. However, we showed that gemcitabine treatment activates cGAS-STING signaling through induction of long terminal repeat (LTR) elements, which consequently induced RELB-mediated non-canonical NFkb signaling. We showed that RELB is a survival factor in DIPG. Remarkably, through small scale drug screen, we found that fimepbinostat has the synergism with gemcitabine to prevent cell growth, mainly by suppressing RELB-mediated non-canonical NFkb signaling. |
