ArticleOncotarget2015
Point mutations of the mTOR-RHEB pathway in renal cell carcinoma.
Article in Oncotarget, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 78 citations in OpenAlex.
- A phase II study of sapanisertib (TAK-228) a mTORC1/2 inhibitor in rapalog-resistant advanced pancreatic neuroendocrine tumors (PNET): ECOG-ACRIN EA2161.Investigational new drugs · 2022Trial
- The role of mTORC2/RICTOR in immune cells and inflammatory diseases.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Review
- Article
- Drug resistant epilepsy driven byEpilepsy & behavior reports · 2026Article
- The mechanism of the PI3K-AKT-mTOR signaling pathway in renal cell carcinoma: current developments and future prospects.Frontiers in oncology · 2026Review
- Article
- Multifocal, multiphenotypic tumours arising from an MTOR mutation acquired in early embryogenesis.Oncogene · 2024Article
- Therapeutic advances of targeting receptor tyrosine kinases in cancer.Signal transduction and targeted therapy · 2024Review
- Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease.Signal transduction and targeted therapy · 2023Review
- VSIG2 promotes malignant progression of pancreatic ductal adenocarcinoma by enhancing LAMTOR2-mediated mTOR activation.Cell communication and signaling : CCS · 2023Article
- 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
- TSC-insensitive Rheb mutations induce oncogenic transformation through a combination of constitutively active mTORC1 signalling and proteome remodelling.Cellular and molecular life sciences : CMLS · 2021Article
- Genomic and Transcriptome Analysis to Identify the Role of the mTOR Pathway in Kidney Renal Clear Cell Carcinoma and Its Potential Therapeutic Significance.Oxidative medicine and cellular longevity · 2021Article
- DEPTOR in Skeletal Development and Diseases.Frontiers in genetics · 2021Review
- In Silico Analyses and Cytotoxicity Study of Asiaticoside and Asiatic Acid from Malaysian Plant as Potential mTOR Inhibitors.Molecules (Basel, Switzerland) · 2020Article
- Rheb1-Independent Activation of mTORC1 in Mammary Tumors Occurs through Activating Mutations in mTOR.Cell reports · 2020Article
- Upregulation of Neuronal Rheb(S16H) for Hippocampal Protection in the Adult Brain.International journal of molecular sciences · 2020Review
- Nanotechnology-Based Targeting of mTOR Signaling in Cancer.International journal of nanomedicine · 2020Review
- Brain somatic mutations in MTOR reveal translational dysregulations underlying intractable focal epilepsy.The Journal of clinical investigation · 2019Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
Aberrations in the mTOR (mechanistic target of rapamycin) axis are frequently reported in cancer. Using publicly available tumor genome sequencing data, we identified several point mutations in MTOR and its upstream regulator RHEB (Ras homolog enriched in brain) in patients with clear cell renal cell carcinoma (ccRCC), the most common histology of kidney cancer. Interestingly, we found a prominent cluster of hyperactivating mutations in the FAT (FRAP-ATM-TTRAP) domain of mTOR in renal cell carcinoma that led to an increase in both mTORC1 and mTORC2 activities and led to an increased proliferation of cells. Several of the FAT domain mutants demonstrated a decreased binding of DEPTOR (DEP domain containing mTOR-interacting protein), while a subset of these mutations showed altered binding of the negative regulator PRAS40 (proline rich AKT substrate 40). We also identified a recurrent mutation in RHEB in ccRCC patients that leads to an increase in mTORC1 activity. In vitro characterization of this RHEB mutation revealed that this mutant showed considerable resistance to TSC2 (Tuberous Sclerosis 2) GAP (GTPase activating protein) activity, though its interaction with TSC2 remained unaltered. Mutations in the FAT domain of MTOR and in RHEB remained sensitive to rapamycin, though several of these mutations demonstrated residual mTOR kinase activity after treatment with rapamycin at clinically relevant doses. Overall, our data suggests that point mutations in the mTOR pathway may lead to downstream mTOR hyperactivation through multiple different mechanisms to confer a proliferative advantage to a tumor cell.
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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.