| Autor: |
Bora Lim, Christine B. Peterson, Alexander Davis, Elin Cho, Troy Pearson, Huey Liu, Minha Hwang, Naoto Tada Ueno, Jangsoon Lee |
| Jazyk: |
angličtina |
| Rok vydání: |
2021 |
| Předmět: |
|
| Zdroj: |
Biomedicines, Vol 9, Iss 10, p 1410 (2021) |
| Druh dokumentu: |
article |
| ISSN: |
2227-9059 |
| DOI: |
10.3390/biomedicines9101410 |
| Popis: |
Triple-negative breast cancer (TNBC) is a heterogeneous group of estrogen, progesterone, and HER2-negative breast cancers with poor clinical outcomes. The imipridone ONC201 is a G-protein-coupled dopamine receptor D2 modulator and an allosteric agonist of the mitochondrial protease caseinolytic protease P(ClpP), which induces apoptosis. Here, we aimed to develop a novel ONC201-based combination therapy targeting TNBC. We performed a reverse-phase protein array analysis of ONC201-treated/-untreated and -sensitive/-resistant cell lines to identify potential predictive biomarkers. A principal component analysis using measured protein expression levels, the apoptosis score (AS), and heatmaps of all the measured protein and AS-related protein expression levels did not show a clear correlation between the expression levels of a specific protein and ONC201 efficacy. Three-dimensional RNA interference kinome-wide library screening revealed the MAPK and PI3K/Akt pathways as potential synergistic therapeutic partners. The combination with the MEK inhibitor trametinib successfully inhibited the growth of both ONC201-sensitive/-resistant TNBC cell lines. The baseline ClpP level correlated with the efficacy of single-agent ONC201. Single and combination therapy increased caspase 3/7 activity. The predictive biomarkers and a detailed mechanism of synergy beyond an induction of caspase activation should be tested for translation into future studies. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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