ONC201/TIC10 enhances durability of mTOR inhibitor everolimus in metastatic ER+ breast cancer
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eLife assessment
This study presents a valuable finding on the combination treatment of ONC201/TIC10 with everolimus for metastatic ER+ breast cancer. The evidence supporting the claims of the authors is solid. The work will be of interest to medical biologists working on breast cancer.
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Abstract
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.
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eLife assessment
This study presents a valuable finding on the combination treatment of ONC201/TIC10 with everolimus for metastatic ER+ breast cancer. The evidence supporting the claims of the authors is solid. The work will be of interest to medical biologists working on breast cancer.
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Reviewer #1 (Public Review):
ONC201/TIC10 refers to the imipridone class of inhibitors which is currently being evaluated in clinical trials for solid tumors. The present manuscript explored the combination treatment of ONC201/TIC10 with everolimus in ER+ breast cancer cell lines. The authors demonstrated the increased therapeutic response by ONC201/TIC10 in primary patient cells progressing on everolimus. The authors show that ONC201/TIC10, in metastatic ER+ breast cancer cells, mechanistically involves oxidative phosphorylation inhibition and stress response activation.
The manuscript provides evidence for the following:
1. ONC201/TIC10 inhibits the proliferation of breast cancer cell lines sensitive and resistant to everolimus.
2. ONC201/TIC10 increased therapeutic response in primary patient cells progressing on everolimus.
3. …Reviewer #1 (Public Review):
ONC201/TIC10 refers to the imipridone class of inhibitors which is currently being evaluated in clinical trials for solid tumors. The present manuscript explored the combination treatment of ONC201/TIC10 with everolimus in ER+ breast cancer cell lines. The authors demonstrated the increased therapeutic response by ONC201/TIC10 in primary patient cells progressing on everolimus. The authors show that ONC201/TIC10, in metastatic ER+ breast cancer cells, mechanistically involves oxidative phosphorylation inhibition and stress response activation.
The manuscript provides evidence for the following:
1. ONC201/TIC10 inhibits the proliferation of breast cancer cell lines sensitive and resistant to everolimus.
2. ONC201/TIC10 increased therapeutic response in primary patient cells progressing on everolimus.
3. ONC201/TIC10, in metastatic ER+ breast cancer cells, mechanistically involves oxidative phosphorylation inhibition and stress response activation
The main merit of the manuscript is that the authors demonstrated that the combination treatment of ONC201/TIC10 with everolimus might be a therapeutic choice for ER+ breast cancer, particular for those resistant to everolimus. This is rather interesting with potential translational impact for breast cancer patients. The major weakness of the manuscript is that some conclusions of the manuscript require rigorous validation. In particular, the therapeutic potential of the combination treatment of ONC201/TIC10 with everolimus needs to be further explored. Some serious work should be done to amend the manuscript before any further consideration. -
Reviewer #2 (Public Review):
In this work, the authors examine the antineoplastic effects of a combined treatment with the impridone ONC201/Tic10 and everolimus against ER+ breast cancer models. The combination was shown to have enhanced activity against everolimus resistant cells especially in 3D models as well as against primary cells derived from patients that have received treatment with everolimus in the past.
The authors address the important issue of drug resistance in ER+ breast cancer by using resistant cell models. Moreover, patient-derived cells were used in this work. From a molecular point of view, current mechanisms of action of ONC201/Tic10 were explored including effects on ERK/AKT pathways, integrated stress response and oxphos. Overall, this interesting work opens a venue for further exploration of imipridones in ER+ …
Reviewer #2 (Public Review):
In this work, the authors examine the antineoplastic effects of a combined treatment with the impridone ONC201/Tic10 and everolimus against ER+ breast cancer models. The combination was shown to have enhanced activity against everolimus resistant cells especially in 3D models as well as against primary cells derived from patients that have received treatment with everolimus in the past.
The authors address the important issue of drug resistance in ER+ breast cancer by using resistant cell models. Moreover, patient-derived cells were used in this work. From a molecular point of view, current mechanisms of action of ONC201/Tic10 were explored including effects on ERK/AKT pathways, integrated stress response and oxphos. Overall, this interesting work opens a venue for further exploration of imipridones in ER+ breast cancer resistant to current first- and second-line therapies.
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