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.
Highlights
To define the ONC201-sensitive and non-sensitive triplenegative breast cancer (TNBC) cell line, we referred to the Greer et al report that the ONC201 IC50 in solid tumors sensitive to this agent was about
We confirmed our hypothesis that the treatment with ONC201 in combination with the MEK inhibitor trametinib synergistically inhibits the growth of TNBC cells regardless of
The caseinolytic protease P (ClpP) expression level in TNBC cells at the baseline correlated with ONC201 sensitivity, which could be rescued by the administration of siRNA ClpP, yet the combination of ONC201 and trametinib did not reduce the expression of ClpP further
Summary
New targeted therapeutics, such as sacituzumab govitecan-hziy (anti-TROP2 antibody-drug conjugate) [1] and immunotherapeutics, have been effective against triplenegative breast cancer (TNBC) [2], patients still suffer from therapy resistance and disease progression. The evasion of apoptosis is a critical mechanism of therapy resistance of cancers, even more so of cancers with TP53 alterations. About 83% of TNBCs harbor TP53 mutations or functional TP53 loss due to the loss of heterozygosity [3]. We hypothesized that inducing apoptosis would be an essential therapeutic strategy for TNBC. Researchers are actively developing mitochondrial apoptosis-inducing therapeutics for breast cancers. Balko et al [4] reported that MCL1 was amplified in about 58% of residual
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