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. Gotink1,2, Henk J. Broxterman1, Richard J. Honeywell1, Henk Dekker1, Richard R. de Haas1, Kiersten M. Miles2, Remi Adelaiye2, Arjan W. Griffioen1, Godefridus J. Peters1, Roberto Pili2 and Henk M.W. Verheul1

1 Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands

2 Department of Medicine, Genitourinary Section, Roswell Park Cancer Institute, Buffalo, NY, USA


Henk M.W. Verheul, email:

Keywords: Sunitinib, resistance, lysosomes, angiogenesis, host-factors

Received: November 12, 2014 Accepted: December 14, 2014 Published: December 15, 2014


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 host-factors may play a crucial role in acquired resistance to sunitinib in vivo.

PII: 106