Synergistic anti-proliferative activity of JQ1 and GSK2801 in triple-negative breast cancer
Nanda Kumar Yellapu1,2, Thuc Ly2,3, Mihaela E Sardiu1,2
1Department of Biostatistics & Data Science, University of Kansas, Medical Center, KS, Kansas City, USA.
Background:
Triple-negative breast cancer (TNBC) constitutes 10-20% of breast cancers and is challenging to treat due to a lack of effective targeted therapies. Previous studies in TNBC cell lines showed in vitro growth inhibition when JQ1 or GSK2801 were administered alone, and enhanced activity when co-administered. Given their respective mechanisms of actions, we hypothesized the combinatorial effect could be due to the target genes affected. Hence the target genes were characterized for their expression in the TNBC cell lines to prove the combinatorial effect of JQ1 and GSK2801.
Methods:
RNASeq data sets of TNBC cell lines (MDA-MB-231, HCC-1806 and SUM-159) were analyzed to identify the differentially expressed genes in single and combined treatments. The topmost downregulated genes were characterized for their downregulated expression in the TNBC cell lines treated with JQ1 and GSK2801 under different dose concentrations and combinations. The optimal lethal doses were determined by cytotoxicity assays. The inhibitory activity of the drugs was further characterized by molecular modelling studies.
Results:
Global expression profiling of TNBC cell lines using RNASeq revealed different expression patterns when JQ1 and GSK2801 were co-administered. Functional enrichment analyses identified several metabolic pathways (i.e., systemic lupus erythematosus, PI3K-Akt, TNF, JAK-STAT, IL-17, MAPK, Rap1 and signaling pathways) enriched with upregulated and downregulated genes when combined JQ1 and GSK2801 treatment was administered. RNASeq identified downregulation of PTPRC, MUC19, RNA5-8S5, KCNB1, RMRP, KISS1 and TAGLN (validated by RT-qPCR) and upregulation of GPR146, SCARA5, HIST2H4A, CDRT4, AQP3, MSH5-SAPCD1, SENP3-EIF4A1, CTAGE4 and RNASEK-C17orf49 when cells received both drugs. In addition to differential gene regulation, molecular modelling predicted binding of JQ1 and GSK2801 with PTPRC, MUC19, KCNB1, TAGLN and KISS1 proteins, adding another mechanism by which JQ1 and GSK2801 could elicit changes in metabolism and proliferation.
Conclusion:
JQ1-GSK2801 synergistically inhibits proliferation and results in selective gene regulation. Besides suggesting that combinatorial use could be useful therapeutics for the treatment of TNBC, the findings provide a glimpse into potential mechanisms of action for this combination therapy approach.
Insights
Combination therapy with JQ1 and GSK2801 synergistically inhibits triple-negative breast cancer (TNBC) cell proliferation. This approach selectively regulates gene expression, offering a potential new therapeutic strategy for TNBC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Triple-negative breast cancer (TNBC) presents a significant therapeutic challenge due to the absence of targeted treatments.
- Previous research indicated that JQ1 and GSK2801 inhibit TNBC cell growth individually, with enhanced effects upon co-administration.
Purpose of the Study:
- To investigate the underlying mechanisms of the synergistic effect of JQ1 and GSK2801 in TNBC.
- To characterize the gene expression profiles and identify target genes affected by the combination therapy.
Main Methods:
- RNA sequencing (RNASeq) was employed to analyze gene expression in TNBC cell lines (MDA-MB-231, HCC-1806, SUM-159) under single and combined JQ1/GSK2801 treatments.
- Cytotoxicity assays determined optimal drug doses, while molecular modeling predicted drug-protein interactions.
Main Results:
- Co-administration of JQ1 and GSK2801 resulted in distinct gene expression patterns and modulated various signaling pathways, including PI3K-Akt and MAPK.
- Key genes such as PTPRC, MUC19, KCNB1, KISS1, and TAGLN were significantly downregulated, while others like GPR146 and SCARA5 were upregulated.
- Molecular modeling suggested direct binding of JQ1 and GSK2801 to proteins including PTPRC, MUC19, KCNB1, TAGLN, and KISS1.
Conclusions:
- The combination of JQ1 and GSK2801 demonstrates synergistic inhibition of TNBC proliferation through selective gene regulation.
- This combinatorial approach holds promise as a potential therapeutic strategy for TNBC.
- The study provides insights into the molecular mechanisms driving the efficacy of this combination therapy.
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