Sphingosine kinase-1 activation causes acquired resistance against Sunitinib in renal cell carcinoma cells

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Hui Gao1, Lichun Deng

  • 1Medical College, Qingdao University, Qingdao, 266023, Shandong, China.

Cell Biochemistry and Biophysics
|August 27, 2013
PubMed

Insights

Acquired resistance to Sunitinib, a cancer drug, is common. This study found that activating SK1 and ERK pathways contributes to Sunitinib resistance in renal cell carcinoma, offering new therapeutic targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Sunitinib is a multi-target tyrosine kinase inhibitor used for metastatic renal cell carcinoma.
  • Acquired resistance limits Sunitinib's long-term efficacy in many cancer patients.
  • The precise molecular mechanisms driving Sunitinib resistance are not fully understood.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying acquired resistance to Sunitinib in renal cell carcinoma.
  • To establish Sunitinib-resistant cell lines for mechanistic studies.
  • To identify potential targets for overcoming Sunitinib resistance.

Main Methods:

  • Established Sunitinib-resistant human renal cell lines (786-O, A498, ACHN, CAKI1) through continuous Sunitinib exposure.
  • Analyzed the expression of platelet-derived growth factor receptor beta (PDGFR-β).
  • Assessed the activation status of Sphingosine kinase 1 (SK1) and Extracellular signal-regulated kinase (ERK).

Main Results:

  • PDGFR-β expression appeared to confer protection against the development of Sunitinib resistance.
  • Both SK1 and ERK pathways were found to be activated in Sunitinib-resistant cell lines.
  • Inhibition of SK1 and ERK successfully resensitized resistant cell lines to Sunitinib.

Conclusions:

  • Activation of SK1 and ERK signaling is a characteristic feature of Sunitinib-resistant renal cell carcinoma.
  • These activated pathways represent an alternative mechanism for evading Sunitinib's anti-tumor effects.
  • Targeting SK1 and ERK may offer a strategy to overcome acquired resistance to Sunitinib.

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