LGG-14. MULTI-OMIC ANALYSIS OF MAPK ACTIVATION IN PEDIATRIC PILOCYTIC ASTROCYTOMA

Abstract

Pilocytic astrocytomas (PA) are low-grade gliomas (pLGG) and are the most frequent childhood brain tumors. They are characterized by oncogene-induced senescence (OIS) initiated and sustained by senescence-associated secretory phenotype (SASP) factors. OIS and SASP in PA are thought to be driven by aberrations of the mitogen-activated protein kinase (MAPK) pathway (e.g. KIAA1549:BRAF fusion, BRAFV600E mutation, for the most common MAPK alterations occuring in PA), leading to its sustained activation. The MAPK pathway cascade is activated in a sequential manner: 1) ERK activation, which phosphorylates downstream partners in both cytoplasm and nucleus. 2) ERK-mediated induction of immediate early genes encoding transcription factors. 3) Induction of MAPK target genes expression. 4) Activation of downstream pathways. Our aim is to unravel the molecular partners involved at each level of the sustained MAPK pathway activation in pLGG with different genetic backgrounds (KIAA1549:BRAF fusion and BRAFV600E mutation), and leading to the induction of OIS and SASP factors expression. pLGG cell lines DKFZ-BT66 (KIAA1549:BRAF) and BT-40 (BRAFV600E) were treated with the MEK inhibitor trametinib at key time points, and gene expression profile analysis was performed, allowing transcriptome analysis at each step of the MAPK cascade. This will be combined with a whole proteomic and phospho-proteomic analysis. Combination of the transcriptome and proteome data layers will allow the identification of a) downstream targetable partners activated by the MAPK pathway involved in PA senescence, b) new putative targets that might bring benefit in combination with MAPK inhibitors.