ArticleThe Journal of clinical investigation2016
Mechanistically distinct cancer-associated mTOR activation clusters predict sensitivity to rapamycin.
Article in The Journal of clinical investigation, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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Who cites it
62 citing papers in PubMed, 95 citations in OpenAlex.
- Exemestane plus everolimus and palbociclib in metastatic breast cancer: clinical response and genomic/transcriptomic determinants of resistance in a phase I/II trial.Nature communications · 2024Trial
- Cancer treatment alters mutant selection in normal esophagus.Nature genetics · 2026Article
- Divergent signaling profiles in mTOR gain-of-function Smith-Kingsmore syndrome (SKS) and TSC2 deficiency.bioRxiv : the preprint server for biology · 2026Article
- The mechanism of the PI3K-AKT-mTOR signaling pathway in renal cell carcinoma: current developments and future prospects.Frontiers in oncology · 2026Review
- The effect of PDLIM7 on cell proliferation, migration, and drug sensitivity in clear cell renal cell carcinoma.Scientific reports · 2025Article
- mTOR Variants Activation Discovers PI3K-like Cryptic Pocket, Expanding Allosteric, Mutant-Selective Inhibitor Designs.Journal of chemical information and modeling · 2025Article
- Multifocal, multiphenotypic tumours arising from an MTOR mutation acquired in early embryogenesis.Oncogene · 2024Article
- Exploring the Complexity and Promise of Tumor Immunotherapy in Drug Development.International journal of molecular sciences · 2024Review
- Article
- Phosphorylation of OTUB1 at Tyr 26 stabilizes the mTORC1 component, Raptor.Cell death and differentiation · 2023Article
- Inhibition of the AKT/mTOR pathway negatively regulates PTEN expression via miRNAs.Acta biochimica et biophysica Sinica · 2022Article
- Activating mTOR Mutations Are Detrimental in Nutrient-Poor Conditions.Cancer research · 2022Article
- Allostery: Allosteric Cancer Drivers and Innovative Allosteric Drugs.Journal of molecular biology · 2022Review
- Germline and sporadic mTOR pathway mutations in low-grade oncocytic tumor of the kidney.Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc · 2022Article
- Emergence of mTOR mutation as an acquired resistance mechanism to AKT inhibition, and subsequent response to mTORC1/2 inhibition.NPJ precision oncology · 2021Article
- Regulation of human mTOR complexes by DEPTOR.eLife · 2021Article
- Functional and structural analyses of novel Smith-Kingsmore Syndrome-Associated MTOR variants reveal potential new mechanisms and predictors of pathogenicity.PLoS genetics · 2021Article
- Targeting nucleotide metabolism as the nexus of viral infections, cancer, and the immune response.Science advances · 2021Review
- A Web of Science-based scientometric analysis about mammalian target of rapamycin signaling pathway in kidney disease from 1986 to 2020.Translational andrology and urology · 2021Article
- NVP-BEZ235 Inhibits Renal Cell Carcinoma by Targeting TAK1 and PI3K/Akt/mTOR Pathways.Frontiers in pharmacology · 2021Article
2 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
15 authors at 5 institutions in 2 countries.
Funding
Abstract
Genomic studies have linked mTORC1 pathway-activating mutations with exceptional response to treatment with allosteric inhibitors of mTORC1 called rapalogs. Rapalogs are approved for selected cancer types, including kidney and breast cancers. Here, we used sequencing data from 22 human kidney cancer cases to identify the activating mechanisms conferred by mTOR mutations observed in human cancers and advance precision therapeutics. mTOR mutations that clustered in focal adhesion kinase targeting domain (FAT) and kinase domains enhanced mTORC1 kinase activity, decreased nutrient reliance, and increased cell size. We identified 3 distinct mechanisms of hyperactivation, including reduced binding to DEP domain-containing MTOR-interacting protein (DEPTOR), resistance to regulatory associated protein of mTOR-mediated (RAPTOR-mediated) suppression, and altered kinase kinetics. Of the 28 mTOR double mutants, activating mutations could be divided into 6 complementation groups, resulting in synergistic Rag- and Ras homolog enriched in brain-independent (RHEB-independent) mTORC1 activation. mTOR mutants were resistant to DNA damage-inducible transcript 1-mediated (REDD1-mediated) inhibition, confirming that activating mutations can bypass the negative feedback pathway formed between HIF1 and mTORC1 in the absence of von Hippel-Lindau (VHL) tumor suppressor expression. Moreover, VHL-deficient cells that expressed activating mTOR mutants grew tumors that were sensitive to rapamycin treatment. These data may explain the high incidence of mTOR mutations observed in clear cell kidney cancer, where VHL loss and HIF activation is pathognomonic. Our study provides mechanistic and therapeutic insights concerning mTOR mutations in human diseases.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.