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Rapamycin (sirolimus), a naturally occurring macrolide, is the only therapeutic approved for women with lymphangioleiomyomatosis (LAM), a progressive, destructive lung disease caused by TSC gene mutations and mTORC1 hyperactivation. However, on cessation of the drug, lung function decline continues. We demonstrated here that pulmonary LAM cancer stem-like state (SLS) cells most highly expressed the eIF4E (eukaryotic translation initiation factor 4E)-dependent translation initiation genes. We also showed that the 4E-BP1 (eukaryotic initiation factor 4E-binding protein 1) gene has the lowest expression in these cells, indicating that the 4E-BP1\/eIF4E ratio in LAM SLS cells favors unrestrained eIF4E oncogenic mRNA translation. The bi-steric mTORC1-selective compound RMC-5552 prevented growth of LAM-associated fibroblasts and phosphorylation of proteins in the ribosomal protein S6K1\/ribosomal protein S6 (S6K1\/S6) and 4E-BP1\/eIF4E translation mTORC1-driven pathways, whereas rapamycin only blocked the S6K\/S6 axis. Rapamycin inhibition of LAM-associated fibroblast growth was rapidly reversed, but RMC-5552 inhibition was more durable. RMC-5552, through its potential to eradicate LAM cancer SLS cells, may have therapeutic benefit in LAM and other diseases with mTORC1 hyperactivity.<\/jats:p>","DOI":"10.1165\/rcmb.2024-0242oc","type":"journal-article","created":{"date-parts":[[2024,11,12]],"date-time":"2024-11-12T16:39:51Z","timestamp":1731429591000},"page":"643-652","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":11,"title":["The Bi-steric Inhibitor RMC-5552 Reduces mTORC1 Signaling and Growth in Lymphangioleiomyomatosis"],"prefix":"10.1093","volume":"72","author":[{"given":"Jilly F.","family":"Evans","sequence":"first","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine"},{"name":"Lung Biology Institute, Perelman School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Owen A.","family":"Ledwell","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine"},{"name":"Lung Biology Institute, Perelman School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Tang","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Massachusetts; 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and"},{"name":"Department of Respiratory Medicine, National Reference Centre for Rare Pulmonary Diseases, Hospices Civils de Lyon, Universit\u00e9 Lyon 1, UMR754, INRAE, ERN-LUNG, Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan M.","family":"Lin","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine"},{"name":"Lung Biology Institute, Perelman School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanth Swaroop","family":"Vanka","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine"},{"name":"Lung Biology Institute, Perelman School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4716-1285","authenticated-orcid":false,"given":"Maria C.","family":"Basil","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine"},{"name":"Lung Biology Institute, Perelman School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1105-0129","authenticated-orcid":false,"given":"Edward","family":"Cantu","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Surgery, University of Pennsylvania, Philadelphia, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7978-6699","authenticated-orcid":false,"given":"Elizabeth P.","family":"Henske","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Massachusetts; 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