ArticleOncogene2023
A bi-steric mTORC1-selective inhibitor overcomes drug resistance in breast cancer.
Article in Oncogene, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 15 citations in OpenAlex.
- Breast cancer-associated fibroblast-derived exosomal miR-1290 promotes triple-negative breast cancer cell proliferation.Signal transduction and targeted therapy · 2026Article
- Critical role for the TGF-β1/mTORC1 signaling axis in defining the transcriptional identity of CTHRC1Science advances · 2026Article
- Article
- The latest progress of personalized drug screening and therapy research for common clinical tumors through the PDX model platform.Journal of pharmaceutical analysis · 2025Review
- Rewinding the Clock: Emerging Pharmacological Strategies for Human Anti-Aging Therapy.International journal of molecular sciences · 2025Review
- The Bi-steric Inhibitor RMC-5552 Reduces mTORC1 Signaling and Growth in Lymphangioleiomyomatosis.American journal of respiratory cell and molecular biology · 2025Article
- Anticancer Potential of Prebiotics: Targeting Estrogen Receptors and PI3K/AKT/mTOR in Breast Cancer.Biomedicines · 2025Review
- Targeting mTORC1 to promote ferroptosis and apoptosis in endometrial cancer with PI3K-Akt-mTOR pathway mutation.Ferroptosis and oxidative stress · 2025Article
- The PI3K-AKT-mTOR axis persists as a therapeutic dependency in KRASMolecular cancer · 2024Article
- RPTOR blockade suppresses brain metastases of NSCLC by interfering the ceramide metabolism via hijacking YY1 binding.Journal of experimental & clinical cancer research : CR · 2024Article
- TWIST1 Upregulation Is a Potential Target for Reversing Resistance to the CDK4/6 Inhibitor in Metastatic Luminal Breast Cancer Cells.International journal of molecular sciences · 2023Article
- Unmasking the tumourigenic role of SIN1/MAPKAP1 in the mTOR complex 2.Clinical and translational medicine · 2023Review
- PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer.Molecular cancer · 2023Review
- Preclinical evaluation of the third-generation, bi-steric mechanistic target of rapamycin complex 1-selective inhibitor RMC-6272 inNeuro-oncology advancesArticle
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
Activation of the PI3K-mTOR pathway is central to breast cancer pathogenesis including resistance to many targeted therapies. The mTOR kinase forms two distinct complexes, mTORC1 and mTORC2, and understanding which is required for the survival of malignant cells has been limited by tools to selectively and completely impair either subcomplex. To address this, we used RMC-6272, a bi-steric molecule with a rapamycin-like moiety linked to an mTOR active-site inhibitor that displays >25-fold selectivity for mTORC1 over mTORC2 substrates. Complete suppression of mTORC1 by RMC-6272 causes apoptosis in ER+/HER2- breast cancer cell lines, particularly in those that harbor mutations in PIK3CA or PTEN, due to inhibition of the rapamycin resistant, mTORC1 substrate 4EBP1 and reduction of the pro-survival protein MCL1. RMC-6272 reduced translation of ribosomal mRNAs, MYC target genes, and components of the CDK4/6 pathway, suggesting enhanced impairment of oncogenic pathways compared to the partial mTORC1 inhibitor everolimus. RMC-6272 maintained efficacy in hormone therapy-resistant acquired cell lines and patient-derived xenografts (PDX), showed increased efficacy in CDK4/6 inhibitor treated acquired resistant cell lines versus their parental counterparts, and was efficacious in a PDX from a patient experiencing resistance to CDK4/6 inhibition. Bi-steric mTORC1-selective inhibition may be effective in overcoming multiple forms of therapy-resistance in ER+ breast cancers.
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Registered trials
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