Understanding the role of CDK8 in protein synthesis for treating MYC-driven medulloblastoma
Medulloblastoma (MB) is the most common malignant pediatric tumor, accounting for 15-20% of childhood brain tumors. Current multimodal therapies--including surgery and radiochemotherapy--increase long-term survival to 60-80%, but 33% of children diagnosed die in 5 years; the median survival for recurrent MB patients being less than 12 months. Molecular profiling and genetic analysis have categorized MB into 4 subgroups, each associated with distinct genetic alterations, age at onset, and prognosis. Among these groups, patients with MYC-driven MB commonly experience relapse accompanied by metastatic spread and local recurrences, resulting in long-term survival rates of less than 5%. Therefore, there is an urgent need to investigate the molecular mechanisms underlying the oncogenic activity driven by MYC and determine optimal strategies to combat this disease. To systematically identify genes representing therapeutic vulnerabilities in MYC-driven MB, we previously performed a CRISPR-Cas9 screening with a specific focus on 1,140 druggable genes across 3 MB cell lines. Cyclin-dependent kinase 8 (CDK8) emerged as a significantly selected gene crucial for MYC-driven MB growth. CDK8 is a nuclear serine-threonine kinase and a member of the CDK/Cyclin module of the mediator complex, primarily functioning as a transcriptional regulator. It has been identified as an oncogene in various cancer types, but the functional significance of CDK8 has not previously been evaluated in MB.
Project Goal:
We have identified a correlation between elevated CDK8 expression and poor prognosis in MB patients with high MYC expression. Our preliminary data indicated that CDK8 depletion substantially reduces MYC expression and induces pronounced transcriptional changes, consequently impeding the growth of MYC-driven MB and implying an oncogenic role of CDK8 in MB progression. Interestingly, utilizing RNA-Seq with genetic knockdown or pharmacological inhibition of CDK8, we found a notable repression of pathways associated with ribosome biogenesis and mRNA translation. Based on these findings, we hypothesized that targeting CDK8 could be a promising therapeutic approach for treating MYC-driven MB by modulating the signaling related to ribosome biogenesis and protein synthesis. mTOR plays key roles in protein synthesis. To investigate the potential synergistic effect of inhibiting both CDK8 and mTOR pathways, we evaluated the impact of Torin1 (mTOR inhibitor) and SEL120 (CDK8 inhibitor) on MB cells employing the Chou-Talalay model and bliss synergy method. Our results demonstrate that the combination of Torin1 and SEL120 synergistically suppressed cell growth and reduced the expression of markers associated with protein synthesis. Therefore, we propose that inhibition of CDK8 and mTOR may result in enhanced therapeutic outcomes for MYC-driven medulloblastoma.
