Abstract Pilocytic astrocytomas (PA), the most common pediatric low-grade gliomas (pLGGs), are driven by MAPK pathway alterations, resulting in oncogene-induced senescence (OIS) and the senescence-associated secretory phenotype (SASP). This study employs a multi-omics approach to investigate the regulation of OIS and SASP in pLGGs. Using senescent DKFZ-BT66 cells derived from KIAA1549::BRAF-fusion-positive PA, we analyzed molecular responses on the mRNA, protein and phosphoprotein level before and after MEK inhibitor treatment. Multi-omics factor analysis and gene set enrichment analysis identified critical OIS effectors and dysregulated pathways. MAPK inhibitor treatment significantly reduced MAPK activity, OIS, and SASP signatures across omics layers while decreasing sensitivity to senolytic drugs. A pathway network encompassing 190 identified MAPK downstream effectors linked to OIS/SASP was constructed, revealing associations with improved progression-free survival in pLGG patients. Additionally, 35 clinically relevant drugs targeting the hereby identified OIS-associated signaling nodes were screened, with four—targeting SOD1, IRS1, CDK1/2/4, or CK2—validated as potential therapeutic candidates in an independent pLGG model. This comprehensive analysis highlights MAPK-OIS-SASP interdependencies in pLGGs and proposes novel therapeutic strategies warranting further evaluation for these tumors.
Sigaud et al. (Fri,) studied this question.