ArticlePloS one2018
RAPTOR up-regulation contributes to resistance of renal cancer cells to PI3K-mTOR inhibition.
Article in PloS one, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 28 citations in OpenAlex.
- Epitranscriptomic regulation of NVP-BEZ235 resistance in ccRCC via the YTHDF3-SYNM regulatory pathway.Genes & genomics · 2026Article
- Cardamonin suppresses mTORC1/SREBP1 through reducing Raptor and inhibits de novo lipogenesis in ovarian cancer.PloS one · 2025Article
- Transcriptome Analysis Reveals Anti-Cancer Effects of Isorhapontigenin (ISO) on Highly Invasive Human T24 Bladder Cancer Cells.International journal of molecular sciences · 2024Article
- Phosphorylation of AMPKα at Ser485/491 Is Dependent on Muscle Contraction and Not Muscle-Specific IGF-I Overexpression.International journal of molecular sciences · 2023Article
- Phosphorylation of OTUB1 at Tyr 26 stabilizes the mTORC1 component, Raptor.Cell death and differentiation · 2023Article
- Identifying Key Lysosome-Related Genes Associated with Drug-Resistant Breast Cancer Using Computational and Systems Biology Approach.Iranian journal of pharmaceutical research : IJPR · 2022Article
- Crosstalk between autophagy inhibitors and endosome-related secretory pathways: a challenge for autophagy-based treatment of solid cancers.Molecular cancer · 2021Review
- Article
- Regulation and metabolic functions of mTORC1 and mTORC2.Physiological reviews · 2021Review
- RAPTOR promotes colorectal cancer proliferation by inducing mTORC1 and upregulating ribosome assembly factor URB1.Cancer medicine · 2020Article
- Cathepsin K inhibition-induced mitochondrial ROS enhances sensitivity of cancer cells to anti-cancer drugs through USP27x-mediated Bim protein stabilization.Redox biology · 2020Article
- Review
- Cell signaling and cancer: a mechanistic insight into drug resistance.Molecular biology reports · 2019Review
- Article
- Article
- Metabolic Pathways in Kidney Cancer: Current Therapies and Future Directions.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2018Review
- Systems biology-based drug repositioning identifies digoxin as a potential therapy for groups 3 and 4 medulloblastoma.Science translational medicine · 2018Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
The outlook for patients with advanced renal cell cancer (RCC) has been improved by targeted agents including inhibitors of the PI3 kinase (PI3K)-AKT-mTOR axis, although treatment resistance is a major problem. Here, we aimed to understand how RCC cells acquire resistance to PI3K-mTOR inhibition. We used the RCC4 cell line to generate a model of in vitro resistance by continuous culture in PI3K-mTOR kinase inhibitor NVP-BEZ235 (BEZ235, Dactolisib). Resistant cells were cross-resistant to mTOR inhibitor AZD2014. Sensitivity was regained after 4 months drug withdrawal, and resistance was partially suppressed by HDAC inhibition, supporting an epigenetic mechanism. BEZ235-resistant cells up-regulated and/or activated numerous proteins including MET, ABL, Notch, IGF-1R, INSR and MEK/ERK. However, resistance was not reversed by inhibiting or depleting these pathways, suggesting that many induced changes were passengers not drivers of resistance. BEZ235 blocked phosphorylation of mTOR targets S6 and 4E-BP1 in parental cells, but 4E-BP1 remained phosphorylated in resistant cells, suggesting BEZ235-refractory mTORC1 activity. Consistent with this, resistant cells over-expressed mTORC1 component RAPTOR at the mRNA and protein level. Furthermore, BEZ235 resistance was suppressed by RAPTOR depletion, or allosteric mTORC1 inhibitor rapamycin. These data reveal that RAPTOR up-regulation contributes to PI3K-mTOR inhibitor resistance, and suggest that RAPTOR expression should be included in the pharmacodynamic assessment of mTOR kinase inhibitor trials.
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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.