Induction of epithelial-mesenchymal transition via activation of epidermal growth factor receptor contributes to sunitinib resistance in human renal cell carcinoma cell lines

J Pharmacol Exp Ther. 2015 Nov;355(2):152-8. doi: 10.1124/jpet.115.226639. Epub 2015 Aug 25.


Sunitinib is widely used for treating renal cell carcinoma (RCC). However, some patients do not respond to treatment with this drug. We aimed to study the association between sunitinib sensitivity and epithelial-mesenchymal transition (EMT) regulation via epidermal growth factor receptor (EGFR) signaling, which is a mechanism of resistance to anticancer drugs. Three RCC cell lines (786-O, ACHN, and Caki-1) were used, and then we evaluated cell viability, EMT regulatory proteins, and signal transduction with sunitinib treatment. Cell viability of 786-O cells was maintained after treatment with sunitinib. After treatment with sunitinib, EGFR phosphorylation increased in 786-O cells, resulting in an increase in the phosphorylation of extracellular signal-regulated kinase, nuclear translocation of β-catenin, and expression of mesenchymal markers. These results suggest that sunitinib induced EMT via activation of EGFR in 786-O cells, but not in ACHN and Caki-1 cells. Caki-1/SN cells, a resistant cell line generated by continuous exposure to sunitinib, displayed increased phosphorylation of EGFR. Cell viability in the presence of sunitinib was decreased by erlotinib, as the selective inhibitor of EGFR, treatment in 786-O and Caki-1/SN cells. Similarly, erlotinib suppressed sunitinib-induced EGFR activation and upregulated mesenchymal markers. Thus, we postulate that resistance to sunitinib in RCC may be associated with EMT caused by activation of EGFR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Carcinoma, Renal Cell / drug therapy*
  • Cell Line, Tumor / drug effects
  • Cell Survival / drug effects
  • Drug Resistance, Neoplasm*
  • Epithelial-Mesenchymal Transition / drug effects*
  • ErbB Receptors / metabolism*
  • Humans
  • Indoles / pharmacology*
  • Kidney Neoplasms / drug therapy*
  • Pyrroles / pharmacology*
  • Signal Transduction
  • Sunitinib


  • Antineoplastic Agents
  • Indoles
  • Pyrroles
  • ErbB Receptors
  • Sunitinib