RAPTOR up-regulation contributes to resistance of renal cancer cells to PI3K-mTOR inhibition

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...

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Vydáno v:	PloS one Ročník 13; číslo 2; s. e0191890
Hlavní autoři:	Earwaker, Philip, Anderson, Caroline, Willenbrock, Frances, Harris, Adrian L., Protheroe, Andrew S., Macaulay, Valentine M.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Public Library of Science 01.02.2018 Public Library of Science (PLoS)
Témata:	1-Phosphatidylinositol 3-kinase AKT protein Allosteric properties Analysis Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Benzamides Biology and Life Sciences Cancer Cancer cells Cancer therapies Carcinoma, Renal Cell - drug therapy Carcinoma, Renal Cell - metabolism Carcinoma, Renal Cell - pathology Cell culture Cell Line, Tumor Clinical trials Continuous culture Drug dosages Drug resistance Drug Resistance, Neoplasm Enzyme inhibitors Experiments Extracellular signal-regulated kinase Gene expression Genetic aspects Genetic regulation Hematology Histone deacetylase Histone Deacetylase Inhibitors - pharmacology Humans Imidazoles - pharmacology Imidazoles - therapeutic use Inhibition Inhibitors Insulin-like growth factors Kidney cancer Kidney Neoplasms - drug therapy Kidney Neoplasms - metabolism Kidney Neoplasms - pathology Kinases Medicine and Health Sciences Metastasis Morpholines - therapeutic use mRNA Mutation Oncology Passengers Pharmacodynamics Pharmacology Phosphoinositide-3 Kinase Inhibitors Phosphorylation Proteins Pyrimidines Quinolines - pharmacology Quinolines - therapeutic use Rapamycin Regulatory-Associated Protein of mTOR - metabolism Renal cell carcinoma Research and Analysis Methods Signal Transduction - drug effects TOR protein TOR Serine-Threonine Kinases - antagonists & inhibitors Treatment resistance Up-Regulation United Kingdom > UK
ISSN:	1932-6203, 1932-6203
On-line přístup:	Získat plný text
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Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Current address: The Cancer Centre, University Hospitals Birmingham NHS Foundation Trust, Edgbaston, Birmingham, United Kingdom. Competing Interests: The authors have declared that no competing interests exist.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0191890