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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.<\/jats:p>","DOI":"10.7554\/elife.85898","type":"journal-article","created":{"date-parts":[[2023,8,18]],"date-time":"2023-08-18T08:15:11Z","timestamp":1692346511000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.85898","source":"Crossref","is-referenced-by-count":15,"title":["ONC201\/TIC10 enhances durability of mTOR inhibitor everolimus in metastatic ER+ breast cancer"],"prefix":"10.7554","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5038-5875","authenticated-orcid":true,"given":"Elena","family":"Farmaki","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00w6g5w60","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center","place":["Duarte, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aritro","family":"Nath","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00w6g5w60","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center","place":["Duarte, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rena","family":"Emond","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00w6g5w60","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center","place":["Duarte, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimya L","family":"Karimi","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00w6g5w60","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center","place":["Duarte, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vince K","family":"Grolmusz","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00w6g5w60","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center","place":["Duarte, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7784-7785","authenticated-orcid":true,"given":"Patrick A","family":"Cosgrove","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00w6g5w60","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center","place":["Duarte, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4850-0453","authenticated-orcid":true,"given":"Andrea H","family":"Bild","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00w6g5w60","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center","place":["Duarte, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2023,9,29]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3004828","article-title":"Dual inactivation of Akt and ERK by TIC10 signals Foxo3a nuclear translocation, TRAIL gene induction, and potent antitumor effects","volume":"5","author":"Allen","year":"2013","journal-title":"Science Translational Medicine"},{"key":"bib2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-91092-8","article-title":"Microarray analysis reveals ONC201 mediated differential mechanisms of CHOP gene regulation in metastatic and nonmetastatic colorectal cancer cells","volume":"11","author":"Al Madhoun","year":"2021","journal-title":"Scientific Reports"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"520","DOI":"10.1056\/NEJMoa1109653","article-title":"Everolimus in postmenopausal hormone-receptor\u2013positive advanced breast cancer","volume":"366","author":"Baselga","year":"2012","journal-title":"New England Journal of Medicine"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"2407","DOI":"10.18632\/oncotarget.2964","article-title":"Resistance to everolimus driven by epigenetic regulation of MYC in ER+ breast cancers","volume":"6","author":"Bihani","year":"2015","journal-title":"Oncotarget"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1089\/ten.TEB.2009.0676","article-title":"Engineering tumors: a tissue engineering perspective in cancer biology","volume":"16","author":"Burdett","year":"2010","journal-title":"Tissue Engineering. 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