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

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.