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

Cancer Chemother Pharmacol. 2013 May;71(5):1297-307. doi: 10.1007/s00280-013-2129-6. Epub 2013 Mar 12.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • 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
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • dactolisib
  • Sunitinib
  • Sirolimus