title: Benchmarking effects of mTOR, PI3K, and dual PI3K/mTOR inhibitors in hepatocellular and renal cell carcinoma models developing resistance to sunitinib and sorafenib.
abstract: OBJECTIVE
  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.affiliation: AAREC Filia Research, 1 place Paul Verlaine, 92100 Boulogne-Billancourt, France.
authors.forename: Maria
authors.initials: M
authors.lastname: Serova
authors.forename: Armand
authors.initials: A
authors.lastname: de Gramont
authors.forename: Annemilaï
authors.initials: A
authors.lastname: Tijeras-Raballand
authors.forename: Célia
authors.initials: C
authors.lastname: Dos Santos
authors.forename: Maria Eugenia
authors.initials: ME
authors.lastname: Riveiro
authors.forename: Khemaies
authors.initials: K
authors.lastname: Slimane
authors.forename: Sandrine
authors.initials: S
authors.lastname: Faivre
authors.forename: Eric
authors.initials: E
authors.lastname: Raymond
mesh_terms: D000631:Aminopyridines / Q000008:administration & dosage / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D000068338:Everolimus; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000077157:Sorafenib; D000077210:Sunitinib; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: C569670:1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno(3,2-d)pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one; D000631:Aminopyridines; D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007093:Imidazoles; D007211:Indoles; D009025:Morpholines; D046912:Multiprotein Complexes; C571178:NVP-BKM120; D010671:Phenylurea Compounds; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D011804:Quinolines; D009536:Niacinamide; C401859:temsirolimus; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol; D000068338:Everolimus; D000077157:Sorafenib; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; C531198:dactolisib; D000077210:Sunitinib; D020123:Sirolimus