Dataset Information

Systems Pharmacology Screening Reveals Targetable Kinases in Supratentorial Ependymoma Kinases in Supratentorial Ependymomas

ABSTRACT: Ependymomas (EPN) are central nervous system tumors arising from ependymal cells, primarily affecting young children and accounting for 10% of intracranial tumors in children and 4% in adults. Current treatments are limited to surgery and radiotherapy, with chemotherapy providing minimal benefit. Over 70% of supratentorial ependymomas (ST-EPNs) are driven by ZFTARELA fusions (ZFTA-RELAfus), which are associated with poor prognosis. Recent molecular classifications have identified two distinct ST-EPN clusters, E1 and E2, with the E1 cluster predominantly composed of ZFTA-RELAfus tumors. However, effective targeted therapies for these tumors remain lacking. Here, we show that the ZFTA-RELAfus mouse model closely mirrors the human E1 cluster, validating its use for therapeutic discovery. Using this model and a systems polypharmacology approach called Kinome Regularization, we identified mer tyrosine kinase (Mertk) as a key regulator of ZFTA-RELAfus cell viability and proliferation. Genetic depletion or pharmacological inhibition of Mertk reduced cell growth ex vivo and treatment with the clinical-grade Mertk inhibitor significantly suppressed tumor proliferation in vivo. Mechanistically, both human E1 tumors and mouse ZFTA-RELAfus tumors showed elevated Mertk expression, with Mertk inhibition leading to decreased activity of pro-survival pathways. Further, substantial overlap (>80%) between genes upregulated in ZFTA-RELAfus tumors and those downregulated following Mertk inhibition treatment suggest a dependency on Mertkmediated signaling for tumor growth. These findings highlight Mertk as a promising therapeutic target and support the clinical development of Mertk inhibitors for treating human E1 subtype and ZFTA-RELAfus -driven ependymomas.

ORGANISM(S): Mus musculus

PROVIDER: GSE291213 | GEO | 2025/12/30

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Ependymomas are neuroepithelial tumors of the central nervous system (CNS), presenting in both adults and children but accounting for almost 10% of all pediatric CNS tumors and up to 30% of CNS tumors in children under 3 years (Bouffet et al., 2009; McGuire et al., 2009; Rodriguez et al., 2009). In children, most ependymomas arise in the posterior fossa, while most adult ependymomas present around the lower spinal cord and spinal nerve roots. Ependymomas display a wide range of morphological features, and several variants are listed in the World Health Organization (WHO) classification (Ellison et al., 2016). These variants are assigned to three WHO grades (I-III), but the clinical utility of this classification is acknowledged to be limited (Ellison et al., 2011). An increasing understanding of the genomic landscape of ependymoma and the discovery of distinct molecular groups by DNA methylation or gene expression profiling have begun to refine approaches to disease classification and prognostication, but have yet to be translated into clinical routine (Hoffman et al., 2014; Mack et al., 2014; Pajtler et al., 2017; Pajtler et al., 2015; Parker et al., 2014; Wani et al., 2012; Witt et al., 2011). Our comprehensive study of DNA methylation profiling across the entire disease demonstrated three molecular groups for each major anatomic compartment: supratentorial (ST), posterior fossa (PF), and spinal (SP) (Pajtler et al., 2015). In the ST compartment, two molecular groups (ST-EPN-RELA and ST-EPN-YAP1) align with tumors harboring specific genetic alterations, RELA and YAP1 fusion genes, which were initially discovered in a whole genome sequencing study (Parker et al., 2014). Among PF ependymomas, two of three molecular groups, PFA (PF-EPN-A) and PFB (PF-EPN-B), account for nearly all tumors; PF-SE tumors are rare, generally showing the morphology of a subependymoma (Pajtler et al., 2015). PFA tumors are found mainly in infants and young children (median age ≈ 3yrs) and have a relatively poor outcome, while PFB tumors are generally found in young adults (median age ≈ 30yrs) and are associated with a better prognosis (Pajtler et al., 2015; Witt et al., 2011). PFA tumors show few copy number alterations (CNAs), while PFB tumors harbor multiple CNAs that tend to affect entire chromosomes. While recurrent structural variants (SVs) are found in ST ependymomas, recurrent SVs or other mutations, such as single nucleotide variants (SNVs) and insertions or deletions (indels), have not been identified in PF ependymomas to date (Mack et al., 2014; Parker et al., 2014).

Dataset Information

Systems Pharmacology Screening Reveals Targetable Kinases in Supratentorial Ependymoma Kinases in Supratentorial Ependymomas

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets