Reversible Epithelial to Mesenchymal Transition Is Associated with Acquired Resistance to Sunitinib in Patients with Renal Cell Carcinoma: Evidence from a Xenograft Study
HJ Hammers, HM Verheul, B Salumbides, R Sharma, R Pili, GJ Netto. Johns Hopkins University, Baltimore
Background: Tyrosine kinase inhibitors (TKIs) targeting angiogenesis via inhibition of the vascular endothelial growth factor (VEGF) pathway have changed the medical management of metastatic renal cell carcinoma. While the treatment with TKIs have demonstrated clinical benefit these drugs will eventually fail. The potential mechanisms of resistance to TKIs are poorly understood.
Design: To address this question we obtained an excisional biopsy of a skin metastasis from patient with clear cell renal carcinoma who initially had a response on sunitinib and eventually progressed on therapy. Tumor segments were grafted subcutaneously in athymic nude mice. Established xenografts were treated with sunitinib. Tumor size, microvascular density and pericyte coverage were determined. Plasma as well as tissue levels for sunitinib were assessed. A tumor derived cell line was established and assessed in vitro for a potential direct antitumor effects of sunitinib.
Results: To our surprise, xenografts from the patient who progressed on sunitinib regained sensitivity to the drug. At a dose of 40 mg/kg sunitinib caused regression of the subcutaneous tumors. Histology showed a marked reduction in microvascular density and pericyte dysfunction. More interestingly, histological examination of the original skin metastasis revealed evidence of epithelial-to-mesenchymal transition while the xenografts showed reversion to the clear cell phenotype. In vitro studies showed no inhibitory effect on tumor cell growth at pharmacologically relevant concentrations.
Conclusions: The histological examination in this xenograft study suggests that reversible epithelial-to-mesenchymal transition may be associated with acquired tumor resistance to TKIs in patients with clear cell renal carcinoma.
Wednesday, March 24, 2010 9:30 AM
Poster Session V # 212, Wednesday Morning