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Cooperative Targets of Combined mTOR/HDAC Inhibition Promote MYC Degradation

ABSTRACT: Cancer treatments often require combinations of molecularly targeted agents to be effective. mTORi (rapamycin) and HDACi (MS-275/entinostat) inhibitors have been shown to be effective in limiting tumor growth, and here we define part of the cooperative action of this drug combination. More than 60 human cancer cell lines responded synergistically (CI<1) when treated with this drug combination compared to single agents. In addition, a breast cancer patient-derived xenograft, and a BCL-XL plasmacytoma mouse model both showed enhanced responses to the combination compared to single agents. Mice, bearing plasma cell tumors lived an average of 70 days longer on combination treatment compared to single agents. A set of 37 genes cooperatively affected (34 down-regulated; 3 up-regulated) by the combination responded pharmacodynamically in human myeloma cell lines, xenografts, and a P493 model, and were both enriched in tumors, and correlated with prognostic markers in myeloma patient datasets. Genes down-regulated by the combination were overexpressed in several untreated cancers (breast, lung, colon, sarcoma, head and neck, myeloma) compared to normal tissues. The MYC/E2F axis, identified by upstream regulator analyses and validated by immunoblots, was significantly inhibited by the drug combination in several myeloma cell lines. Furthermore, 88% of the 34 genes downregulated have MYC binding sites in their promoters, and the drug combination cooperatively reduced MYC half-life by 55% and increased degradation. Thus, integrative approaches to understand drug synergy identified a clinically actionable strategy to inhibit MYC/E2F activity and tumor cell growth in vivo.

ORGANISM(S): Homo sapiens

PROVIDER: GSE97985 | GEO | 2018/05/01

REPOSITORIES: GEO

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Project description:MYC-driven Group 3 medulloblastoma (MB) (subtype II) is a highly aggressive childhood brain tumor. Sensitivity of MYC-driven MBs to class I histone deacetylase inhibitors (HDACi) has been previously demonstrated in vitro and in vivo. We here characterize the transcriptional effects of class I HDAC inhibition in MYC-driven MB and explore beneficial drug combinations. MYC-amplified Group 3 MB cells (HD-MB03) were treated with class I HDACi entinostat. Changes in the gene expression profile compared to untreated control were quantified on a microarray. Gene set enrichment analysis, cytoscape enrichment mapping and ingenuity pathway analysis led to the identification of pathways affected by entinostat treatment. Five drugs interfering with these pathways (olaparib, idasanutlin, ribociclib, selinexor, vinblastine) were tested as single agents in metabolic activity assays in three MYC-amplified and two non-MYC-amplified MB cell lines. Synergy with entinostat was evaluated by dose response curve shift, combination index and zero interaction potency synergy model and validated in cell count and flow cytometry experiments in two MYC-amplified and one non-MYC-amplified MB cell line. The effect of the most promising drug combination (entinostat and olaparib) on DNA damage was evaluated by γH2A.X quantification in immunoblotting, fluorescence microscopy and flow cytometry. Entinostat treatment changed the expression of genes involved in 22 pathways, including downregulation of DNA damage response. The PARP1 inhibitors olaparib and pamiparib showed synergy with entinostat. The combination of entinostat and olaparib led to increased cell death, decreased viability and increased formation of double strand breaks selectively in MYC-amplified MB cells. MYC-amplified MB cells treated with entinostat and olaparib were particularly vulnerable to additional induction of DNA damage by doxorubicin. Non-MYC-amplified MB cells and normal human fibroblasts were not susceptible to this triple treatment. Our study identifies the combination of entinostat with olaparib and doxorubicin as a new potential therapeutic approach for MYC-driven Group 3 MB.

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Cooperative Targets of Combined mTOR/HDAC Inhibition Promote MYC Degradation

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