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A Combination of Epigenetic BET and CDK9 Inhibitors for Treatment of Human Melanoma

ABSTRACT: The transcriptome of 3 cutaneous melanoma cell lines treated with Control (DMSO), CDK9 inhibitor (CDKI73), BET/bromodomain and extra terminal inhibitors IBET151, or combination of both drugs was assessed using RNAseq. Dysregulation of epigenetic modifiers is a frequent event in melanoma and underlies many aspects of melanoma biology including resistance to targeted and immunotherapies. Here we report that dual targeting of BET and CDK9 proteins have synergistic effects against melanoma cells in vitro and in vivo. The BET inhibitor (IBET151) and CDK9 inhibitor (CDKI73) synergistically killed melanoma cells in vitro independent of their BRAF or NRAS mutation status. The combination of drugs markedly inhibited the growth of human melanoma C002M cells in vitro in 3D spheroids and in vivo in NSG mice compared to vehicle control and the individual drugs (p<0.05). Cell death was associated with mitochondrial depolarisation and caspase dependent apoptosis with cleavage of PARP1 as well as downregulation of anti-apoptotic proteins BCL2, BCLXL and MCL1. GSEA revealed downregulation of hallmark gene-sets associated with E2F, G2M checkpoint and c-MYC. Survival analysis showed worse prognosis with high G2M, E2F or c-MYC gene signatures suggesting biomarkers of response of BET and CDK9 inhibitors in melanoma. This novel combination of epigenetic inhibitors targets multiple downstream genes leading to cell death of melanoma cells in vitro and in vivo and warrant further investigation for treatment of melanoma in patients not responding to current therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE167241 | GEO | 2021/02/23

REPOSITORIES: GEO

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Project description:The first clinical trial testing the combination of targeted therapy with a BRAF inhibitor vemurafenib and immunotherapy with a CTLA-4 antibody ipilimumab was terminated early due to significant liver toxicities, possibly due to paradoxical activation of the MAPK pathway by BRAF inhibitors in tumors with wild type BRAF. MEK inhibitors can potentiate the MAPK inhibition in tumor, while potentially alleviating the unwanted paradoxical MAPK activation. With a mouse model of syngeneic BRAFV600E driven melanoma (SM1), we tested whether the addition of the MEK inhibitor trametinib would enhance the immunosensitization effects of the BRAF inhibitor dabrafenib. Combination of dabrafenib and trametinib with pmel-1 adoptive cell transfer (ACT) showed complete tumor regression. Bioluminescent imaging and tumor infiltrating lymphocyte (TIL) phenotyping showed increased effector infiltration to tumors with dabrafenib, trametinib or dabrafenib plus trametinib with pmel-1 ACT combination. Intracellular IFN gamma staining of the TILs and in vivo cytotoxicity studies showed trametinib was not detrimental to the effector functions in vivo. Dabrafenib increased tumor associated macrophages and T regulatory cells (Tregs) in the tumors, which can be overcome by addition of trametinib. Microarray analysis revealed increased melanoma antigen, MHC expression, and global immune-related gene upregulation with the triple combination therapy. Given the up-regulation of PD-L1 seen with dabrafenib and/or trametinib combined with antigen specific ACT, we tested the triple combination of dabrafenib, trametinib with anti-PD1 therapy, and observed superior anti-tumor effect to SM1 tumors. Our findings support the testing of these combinations in patients with BRAFV600E mutant metastatic melanoma. SM1 tumors were implanted into C57BL/6 mice. Mice were treated by ACT of pmel-1 splenocytes or C57BL/6 splenocytes as control. Pmel-1 treated mice were additionally treated with either vehicle, dabrafenib, trametinib, or combination of both drugs and control mice were treated with vehicle or combination of both drugs.

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A Combination of Epigenetic BET and CDK9 Inhibitors for Treatment of Human Melanoma

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