Acquired tumor cell resistance to sunitinib causes resistance in a HT-29 human colon cancer xenograft mouse model without affecting sunitinib biodistribution or the tumor microvasculature

Kristy J. Gotink, Henk J. Broxterman, Richard J. Honeywell, Henk Dekker, Richard R. de Haas, Kiersten M. Miles, Remi Adelaiye, Arjan W. Griffioen, Godefridus J. Peters, Roberto Pili, Henk M.W. Verheul

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Acquired resistance to anti-angiogenic tyrosine kinase inhibitors is an important clinical problem in treating various cancers. To what extent acquired resistance is determined by microenvironmental host-factors or by tumor cells directly is unknown. We previously found that tumor cells can become resistant to sunitinib in vitro. Here, we studied to what extent in vitro induced resistance of tumor cells determines in vivo resistance to sunitinib. In severe combined immunodeficient mice, tumors were established from HT-29 parental colon cancer cells (HT-29PAR) or the in vitro induced sunitinib resistant HT-29 cells (HT-29SUN). Treatment with sunitinib (40mg/ kg/day) inhibited tumor growth of HT-29PAR tumors by 71±5%, while no inhibition of HT-29SUN tumor growth was observed. Intratumoral sunitinib concentrations and reduced micro vessel density (mvd) were similar in both groups. Ki67 staining revealed that tumor cell proliferation was significantly reduced with 30% in HT-29PAR tumors, but unaffected in HT-29SUN tumors upon sunitinib treatment. The lysosomal capacity reflected by LAMP-1 and -2 expression was higher in HT-29SUN compared to HT-29PAR tumors indicating an increased sequestration of sunitinib in lysosomes of resistant tumors. In conclusion, we demonstrate that tumor cells rather than hostfactors may play a crucial role in acquired resistance to sunitinib in vivo.

Original languageEnglish (US)
Pages (from-to)844-853
Number of pages10
JournalOncoscience
Volume1
Issue number12
DOIs
StatePublished - 2014
Externally publishedYes

Keywords

  • Angiogenesis
  • Host-factors
  • Lysosomes
  • Resistance
  • Sunitinib

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Gotink, K. J., Broxterman, H. J., Honeywell, R. J., Dekker, H., de Haas, R. R., Miles, K. M., Adelaiye, R., Griffioen, A. W., Peters, G. J., Pili, R., & Verheul, H. M. W. (2014). Acquired tumor cell resistance to sunitinib causes resistance in a HT-29 human colon cancer xenograft mouse model without affecting sunitinib biodistribution or the tumor microvasculature. Oncoscience, 1(12), 844-853. https://doi.org/10.18632/oncoscience.106