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While CDK4\/6 inhibitors (CDK4\/6i) combined with endocrine therapy have transformed treatment for metastatic HR\n                    <jats:sup>+<\/jats:sup>\n                    \/HER2\n                    <jats:sup>\u2212<\/jats:sup>\n                    BC, acquired resistance remains a major obstacle. Using HR\n                    <jats:sup>+<\/jats:sup>\n                    \/HER2\n                    <jats:sup>\u2212<\/jats:sup>\n                    BC models with acquired resistance to the CDK4\/6 inhibitors Palbociclib or Ribociclib, we uncovered a metabolic vulnerability in highly resistant clones, mediated by mTORC1 hyperactivation and autophagy suppression. Gene expression profiling revealed enrichment of glycolysis and mTORC1 pathways in CDK4\/6i-resistant cells, which manifested as heightened sensitivity to the metabolic inhibitors Metformin and Dichloroacetate (DCA). Mechanistically, mTORC1 overactivation impaired autophagy via ULK1-Ser757 phosphorylation, as confirmed by LC3 flux assays, leaving resistant cells unable to adapt to energy stress. Treatment with metabolic drugs triggered AMPK activation, ACC inhibition, and PARP cleavage, culminating in apoptosis. Clinically, immunohistochemical analysis of a BC cohort revealed a significant correlation between mTORC1 activity (p4E-BP1\n                    <jats:sup>T37\/46<\/jats:sup>\n                    ) and autophagy suppression (p62 accumulation), supporting the translational relevance of this axis. Our findings propose mTORC1-mediated autophagy defects as a biomarker for metabolic vulnerability in CDK4\/6i-resistant BC, offering a rationale for targeting these tumors with metabolic therapies to overcome resistance.\n                  <\/jats:p>","DOI":"10.1038\/s41419-026-08496-5","type":"journal-article","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T16:35:14Z","timestamp":1771518914000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["mTOR-driven autophagy suppression defines metabolic vulnerability in CDK4\/6 inhibitor-resistant HR+\/HER2\u2212 breast cancer"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-0647-1235","authenticated-orcid":false,"given":"Luise","family":"von Wichert","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina","family":"Stroh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4836-8605","authenticated-orcid":false,"given":"Marie","family":"Witt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Wanzel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Mernberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Griewing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"W\u00fcndisch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berit M.","family":"Pfitzner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3880-1968","authenticated-orcid":false,"given":"Julia","family":"Teply-Szymanski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Sophie","family":"Litmeyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten","family":"Denkert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uwe","family":"Wagner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0134-7826","authenticated-orcid":false,"given":"Thorsten","family":"Stiewe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9015-3646","authenticated-orcid":false,"given":"Niklas","family":"Gremke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,19]]},"reference":[{"key":"8496_CR1","first-page":"229","volume":"74","author":"F Bray","year":"2024","unstructured":"Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. 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CD is cofounder of Sividon Diagnostics. In addition, CD has a patent on VMScope digital pathology software with royalties paid; a patent WO2020109570A1\u2014cancer immunotherapy pending; and patents WO2015114146A1 and WO2010076322A1\u2014therapy response issued. PJ reports research grant and travel expenses from GILEAD Sciences GmbH out-side the submitted work. NH declares to be GBG Forschungs GmbH employee. GBG Forschungs GmbH reports financial funding from AstraZeneca and Myriad during the conduct of the study; received funding for research grants from Abbvie, Amgen, AstraZeneca, BMS, Daiichi-Sankyo, Gilead, Molecular Health, Stemline Menarini, Celgene\/BMS, Novartis, Pfizer and Roche (paid to the institution); GBG Forschungs GmbH has licensing fees from VMscope GmbH. In addition, GBG Forschungs GmbH has a patent EP21152186.9 pending, a patent EP19808852.8 pending, and a patent EP14153692.0 pending. The other authors declare no conflicts of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Immunohistochemical staining and evaluation of breast cancer patient tissue samples were approved by the Ethics Committee of the Charit\u00e9 (Ethics Opinion No. EA1\/139\/05) and conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all patients for the use of their tissue samples in this study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"235"}}