MDB-34. CDK8 inhibition enhances radiotherapy efficacy in MYC -amplified medullloblastoma

Medulloblastoma (MB) is the most common malignant pediatric brain tumor with Group 3 (G3) tumors having the lowest overall survival rate. Using the Pediatric Cancer Dependency Map to screen for therapeutic dependencies, we previously identified cyclin-dependent kinase 8 (CDK8) as the strongest vulnerability in G3 MB compared to all other pediatric tumors. CDK8 expression is significantly elevated in tumors, and its expression correlates with poor prognoses in patients. CDK8 along with its cognate cyclin, Cyclin C, and the Mediator components MED12 and MED13 form the CDK8 kinase module (CKM), which regulate transcription. We reveal that CKM dependency correlates with MYC amplification status. A clinically viable CDK8 inhibitor, SEL120, exhibited low micromolar IC50 and significant antagonization of MYC signaling. Administration of SEL120 in vivo led to a significant reduction in tumor growth in a heterotopic, flank model, however all mice still succumbed to their disease suggesting the need for rational combinations. Transcriptomic analyses after SEL120 administration demonstrated a marked downregulation of DNA repair and p53 signaling, suggesting CDK8 inhibition may combine with therapies that induce DNA damage. Radiotherapy is an essential component of multimodal therapy for MB treatment, but is accompanied by severe long-term sequelae in survivors. The identification of small molecules which enhance radiation efficacy and possibly allow for dose reduction is an unmet need. We next tested the combination of SEL120 and radiation which significantly synergized to target G3 tumor cells and caused no additional toxicity in normal neuronal cells. Recent work revealed that SEL120 penetrates the blood-brain barrier and, although having limited single agent efficacy in our hands, synergized with radiotherapy to significantly extend animal survival effectively eradicating tumors in a subset of mice. In summary, SEL120 treatment enhances radiation-induced cytotoxicity in G3 MB, highlighting CDK8 inhibition as a possible radiosensitizing agent for the treatment of medulloblastoma.