The mTOR inhibitor, everolimus, is an important clinical management component of metastatic ER+ breast cancer (BC). However, most patients develop resistance and progress on therapy, highlighting the need to discover strategies that increase mTOR inhibitor effectiveness. We developed ER+ BC cell lines, sensitive or resistant to everolimus, and discovered that combination treatment of ONC201/TIC10 with everolimus inhibited cell growth in 2D/3D in vitro studies. We confirmed increased therapeutic response in primary patient cells progressing on everolimus, supporting clinical relevance. We show that ONC201/TIC10 mechanism in metastatic ER+ BC cells involves oxidative phosphorylation inhibition and stress response activation. Transcriptomic analysis in everolimus resistant breast patient tumors and mitochondrial functional assays in resistant cell lines demonstrated increased mitochondrial respiration dependency, contributing to ONC201/TIC10 sensitivity. We propose that ONC201/TIC10 and modulation of mitochondrial function may provide an effective add-on therapy strategy for patients with metastatic ER+ BCs resistant to mTOR inhibitors.
