ONC201 and an MEK Inhibitor Trametinib Synergistically Inhibit the Growth of Triple-Negative Breast Cancer Cells
Bora Lim,
Christine B. Peterson,
Alexander Davis,
Elin Cho,
Troy Pearson,
Huey Liu,
Minha Hwang,
Naoto Tada Ueno,
Jangsoon Lee
Affiliations
Bora Lim
Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Christine B. Peterson
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Alexander Davis
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Elin Cho
The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Troy Pearson
Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Huey Liu
Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Minha Hwang
Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Naoto Tada Ueno
Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Jangsoon Lee
Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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.
