Cancer Chemotherapy and Pharmacology

, Volume 71, Issue 5, pp 1297–1307 | Cite as

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

  • Maria Serova
  • Armand de Gramont
  • Annemilaï Tijeras-Raballand
  • Célia Dos Santos
  • Maria Eugenia Riveiro
  • Khemaies Slimane
  • Sandrine Faivre
  • Eric Raymond
Original Article



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.


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.


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.


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.


Kidney cancer mTOR inhibitor Resistance VEGFr tyrosine kinase inhibitor Angiogenesis 

Supplementary material

280_2013_2129_MOESM1_ESM.docx (13 kb)
Supplementary material 1 (DOCX 12 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Maria Serova
    • 1
    • 2
  • Armand de Gramont
    • 1
  • Annemilaï Tijeras-Raballand
    • 1
    • 2
  • Célia Dos Santos
    • 1
    • 2
  • Maria Eugenia Riveiro
    • 2
  • Khemaies Slimane
    • 3
  • Sandrine Faivre
    • 2
  • Eric Raymond
    • 2
  1. 1.AAREC Filia ResearchBoulogne-BillancourtFrance
  2. 2.INSERM U728 and Department of Medical OncologyBeaujon University Hospital (AP-HP–PRES Paris 7 Diderot)ClichyFrance
  3. 3.Novartis Pharma S.A.S.Rueil-MalmaisonFrance

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