Abstract
Medulloblastoma (MB) is the most common malignant brain tumor in children. Patients with MYC-amplified Group 3 MBs exhibit particularly poor survival rates even after intensive therapy, and surviving patients often suffer from long-term sequelae. Poor survival rates and sequelae call for new therapeutic strategies, such as targeted therapy options. We have previously shown that MYC-amplified MBs are sensitive to class I histone deacetylase (HDAC) inhibition. Here we investigate possible combinatorial treatment with HDACi and PLK1i. We evaluated the metabolic activity of MYC-amplified and non-amplified MB, high grade glioma (HGG) and neuroblastoma (NB) cell lines after single and combinatorial treatments with HDACi and PLK1i. The interaction effect was determined by combination index (CI) calculation using the Chou-Talalay method. On-target activity was examined by immunoblotting for pTCTP and H3K27ac. The findings were validated in an inducible MYC cell line. The gene expression profile in the MYC-amplified HD-MB03 cell line was analyzed after MS-275, volasertib or combination treatment. We show that the MYC target gene PLK1 is significantly downregulated upon HDACi treatment. We hypothesized that inhibition of both, HDACs and PLK1 could have synergistic effects. MYC-amplified cell lines were more sensitive than non-amplified cell lines to PLK1i showing 3–10 times lower IC50. PLK1i and HDACi interacted synergistically (CI below 0.9) in lower concentrations in MYC-amplified compared with non-amplified cell lines. Similar results were obtained for MYC or N-MYC-amplified HGG and NB cell lines. MYC target genes were significantly downregulated in the MYC-amplified cell line HD-MB03 after treatment with PLK1i and HDACi. Our data suggests that MYC-amplification is a predictive marker for PLK1i treatment in MB and other entities. The combination of HDACi and PLKi could be a candidate therapy for MYC-amplified group 3 MB, and possibly other tumors harboring MYC amplification, in future clinical trials. Studies investigating the mechanism of action are ongoing.