Abstract
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.
Original language | English (US) |
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Article number | 1410 |
Journal | Biomedicines |
Volume | 9 |
Issue number | 10 |
DOIs | |
State | Published - Oct 2021 |
Keywords
- Apoptosis
- MEK inhibitor
- ONC201
- TNBC
- Trametinib
ASJC Scopus subject areas
- Medicine (miscellaneous)
- General Biochemistry, Genetics and Molecular Biology
MD Anderson CCSG core facilities
- Biostatistics Resource Group
- Cytogenetics and Cell Authentication Core
- Functional Proteomics Reverse Phase Protein Array Core
- Bioinformatics Shared Resource