{"doi":"10.1165/rcmb.2024-0242oc","title":"The Bi-steric Inhibitor RMC-5552 Reduces mTORC1 Signaling and Growth in Lymphangioleiomyomatosis","abstract":"Mutations in the TSC (tuberous sclerosis complex) genes result in the hyperactivation of the mTORC1 (mechanistic/mammalian target of rapamycin 1) growth pathway in mesenchymal pulmonary cells. 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.","journal":"American Journal of Respiratory Cell and Molecular Biology","year":2024,"id":455032,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9548,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1053508,"name":"O. Ledwell","orcid":null,"position":1,"is_corresponding":false},{"id":92231,"name":"Yan Tang","orcid":"0000-0002-6223-8423","position":2,"is_corresponding":false},{"id":323518,"name":"Ryan W. Rue","orcid":"0009-0004-1608-9780","position":3,"is_corresponding":false},{"id":323520,"name":"Alexander R. Mukhitov","orcid":"0000-0001-6443-0788","position":4,"is_corresponding":false},{"id":1278852,"name":"Rémi Diesler","orcid":"0000-0003-0746-357X","position":5,"is_corresponding":false},{"id":323519,"name":"Susan M. Lin","orcid":"0000-0002-2415-8350","position":6,"is_corresponding":false},{"id":1009684,"name":"Kanth Swaroop Vanka","orcid":"0000-0003-3641-2499","position":7,"is_corresponding":false},{"id":228725,"name":"Maria C. Basil","orcid":"0000-0003-4716-1285","position":8,"is_corresponding":false},{"id":260644,"name":"Edward Cantu","orcid":"0000-0003-1105-0129","position":9,"is_corresponding":false},{"id":247628,"name":"Elizabeth P. Henske","orcid":"0000-0001-7978-6699","position":10,"is_corresponding":false},{"id":323524,"name":"Vera P. Krymskaya","orcid":"0000-0002-0584-4486","position":11,"is_corresponding":false},{"id":324752,"name":"Jilly F. Evans","orcid":null,"position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":null,"created_at":"2026-07-19T02:03:17.458329Z","pmid":"39531634","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}