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Molecular Signatures of CB-6644 Inhibition of the RUVBL1/2 Complex in Multiple Myeloma
Weijun Yi1,2, Sebastian A Dziadowicz1, Rachel S Mangano1,3
1Department of Microbiology, Immunology & Cell Biology, West Virginia University, Morgantown, WV 26505, USA.
Abstract:
Multiple myeloma is the second most hematological cancer. RUVBL1 and RUVBL2 form a subcomplex of many chromatin remodeling complexes implicated in cancer progression. As an inhibitor specific to the RUVBL1/2 complex, CB-6644 exhibits remarkable anti-tumor activity in xenograft models of Burkitt's lymphoma and multiple myeloma (MM). In this work, we defined transcriptional signatures corresponding to CB-6644 treatment in MM cells and determined underlying epigenetic changes in terms of chromatin accessibility. CB-6644 upregulated biological processes related to interferon response and downregulated those linked to cell proliferation in MM cells. Transcriptional regulator inference identified E2Fs as regulators for downregulated genes and MED1 and MYC as regulators for upregulated genes. CB-6644-induced changes in chromatin accessibility occurred mostly in non-promoter regions. Footprinting analysis identified transcription factors implied in modulating chromatin accessibility in response to CB-6644 treatment, including ATF4/CEBP and IRF4. Lastly, integrative analysis of transcription responses to various chemical compounds of the molecular signature genes from public gene expression data identified CB-5083, a p97 inhibitor, as a synergistic candidate with CB-6644 in MM cells, but experimental validation refuted this hypothesis.
Insights
CB-6644, a RUVBL1/2 inhibitor, shows anti-tumor effects in multiple myeloma by altering gene expression and chromatin accessibility. It upregulates interferon response and downregulates cell proliferation, offering new therapeutic insights.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Multiple myeloma (MM) is a significant hematological malignancy.
- The RUVBL1/2 complex is implicated in cancer progression.
- CB-6644 is a specific inhibitor of the RUVBL1/2 complex with demonstrated anti-tumor activity.
Purpose of the Study:
- To define transcriptional signatures of CB-6644 treatment in MM cells.
- To investigate epigenetic changes, specifically chromatin accessibility, induced by CB-6644.
- To identify potential synergistic drug candidates with CB-6644.
Main Methods:
- Transcriptional profiling of MM cells treated with CB-6644.
- Chromatin accessibility assays (e.g., ATAC-seq).
- Transcription factor binding site analysis and integrative genomics.
Main Results:
- CB-6644 treatment upregulated interferon response and downregulated cell proliferation pathways in MM cells.
- Transcriptional regulators like E2Fs, MED1, and MYC were identified.
- Chromatin accessibility changes were observed primarily in non-promoter regions, involving factors like ATF4/CEBP and IRF4.
- A potential synergistic candidate, CB-5083, was identified but not experimentally validated.
Conclusions:
- CB-6644 modulates key cellular processes in multiple myeloma through transcriptional and epigenetic mechanisms.
- Understanding these changes provides insights into the drug's mechanism of action.
- Further research is needed to explore combination therapies.
