Benchmarking effects of mTOR, PI3K, and dual PI3K/mTOR inhibitors in hepatocellular and renal cell carcinoma models developing resistance to sunitinib and sorafenib.

Abstract

PURPOSE:

To evaluate first-generation rapamycin analogs (everolimus, temsirolimus, and rapamycin) and second-generation drugs inhibiting mTOR kinase (AZD-8055), PI3K (BKM-120) or both (BEZ-235 and GDC-0980) in hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC) cells characterized for acquired resistance to sorafenib or sunitinib.

METHODS:

Anti-proliferative (MTT assay) and cell signaling (Western blot) effects of rapamycin analogs (1-20 μM) and second-generation drugs (0.03-20.0 μM) were assessed in human HCC SK-HEP1, RCC 786-0, and sorafenib- (SK-Sora) or sunitinib-resistant (786-Suni) cells.

RESULTS:

In SK-HEP1 cells displaying high PTEN and Bcl2 expression, rapamycin analogs had poor anti-proliferative effects. However, SK-Sora cells were more sensitive to rapamycin analogs (≥1 μM) than SK-HEP1 cells. In 786-0 cells, lacking PTEN and Bcl2 expression, ≥1 μM rapamycin analogs blocked mTORC1 signaling, transiently activated Akt, and inhibited cell proliferation. Protracted sunitinib exposure in 786-Suni cells yielded an increase in p27 expression and a decreased sensitivity to rapamycin analogs, although mTORC1 function could be inhibited with rapamycin analogs. Second-generation drugs induced more potent growth inhibition than rapamycin analogs at concentrations >0.03 μM in parental cells, SK-Sora, and 786-Suni cells. Growth inhibitory concentrations of these new drugs also blocked mTORC1 downstream targets.

CONCLUSIONS:

Rapamycin analogs inhibited mTORC1 downstream targets and yielded anti-proliferative effects in HCC and RCC cells. Second-generation drugs also appeared to be potent inhibitors of mTORC1 signaling; however, they appeared to be far more potent in inhibiting cellular proliferation in parental HCC and RCC cells and in cells developing resistance to sorafenib or sunitinib.

• Authors: Maria Serova, Armand de Gramont, Annemilaï Tijeras-Raballand, Célia Dos Santos, Maria Eugenia Riveiro, Khemaies Slimane, Sandrine Faivre, Eric Raymond
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 71 Issue 5 Pg. 1297-307 (May 2013) ISSN: 1432-0843 [Electronic] Germany
• PMID: 23479136 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno(3,2-d)pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one
• Aminopyridines
• Antineoplastic Agents
• Bridged Bicyclo Compounds, Heterocyclic
• Imidazoles
• Indoles
• Morpholines
• Multiprotein Complexes
• NVP-BKM120
• Phenylurea Compounds
• Phosphoinositide-3 Kinase Inhibitors
• Pyrimidines
• Pyrroles
• Quinolines
• Niacinamide
• temsirolimus
• (5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol
• Everolimus
• Sorafenib
• Mechanistic Target of Rapamycin Complex 1
• TOR Serine-Threonine Kinases
• dactolisib
• Sunitinib
• Sirolimus

Topics

• Aminopyridines (administration & dosage, pharmacology)
• Antineoplastic Agents (administration & dosage, pharmacology)
• Bridged Bicyclo Compounds, Heterocyclic (administration & dosage, pharmacology)
• Carcinoma, Hepatocellular (drug therapy, pathology)
• Carcinoma, Renal Cell (drug therapy, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm
• Everolimus
• Humans
• Imidazoles (administration & dosage, pharmacology)
• Indoles (pharmacology)
• Kidney Neoplasms (drug therapy, pathology)
• Liver Neoplasms (drug therapy, pathology)
• Mechanistic Target of Rapamycin Complex 1
• Morpholines (administration & dosage, pharmacology)
• Multiprotein Complexes (antagonists & inhibitors)
• Niacinamide (analogs & derivatives, pharmacology)
• Phenylurea Compounds (pharmacology)
• Phosphoinositide-3 Kinase Inhibitors
• Pyrimidines (administration & dosage, pharmacology)
• Pyrroles (pharmacology)
• Quinolines (administration & dosage, pharmacology)
• Signal Transduction (drug effects)
• Sirolimus (administration & dosage, analogs & derivatives, pharmacology)
• Sorafenib
• Sunitinib
• TOR Serine-Threonine Kinases (antagonists & inhibitors)