Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma: evidence from a xenograft study.
Tyrosine kinase inhibitors (TKI) targeting angiogenesis via inhibition of the vascular endothelial growth factor pathway have changed the medical management of metastatic renal cell carcinoma. Although treatment with TKIs has shown clinical benefit, these drugs will eventually fail patients. The potential mechanisms of resistance to TKIs are poorly understood. To address this question, we obtained an excisional biopsy of a skin metastasis from a patient with clear cell renal carcinoma who initially had a response to sunitinib and eventually progressed with therapy. Tumor pieces were grafted s.c. 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 potential direct antitumor effects of sunitinib. 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, histologic examination of the original skin metastasis revealed evidence of epithelial to mesenchymal transition, whereas the xenografts showed reversion to the clear cell phenotype. In vitro studies showed no inhibitory effect on tumor cell growth at pharmacologically relevant concentrations. In conclusion, the histologic 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.
Hammers
Hans J
HJ
Johns Hopkins University, Baltimore, Maryland, USA.
Verheul
Henk M
HM
Salumbides
Brenda
B
Sharma
Rajni
R
Rudek
Michelle
M
Jaspers
Janneke
J
Shah
Preeti
P
Ellis
Leigh
L
Shen
Li
L
Paesante
Silvia
S
Dykema
Karl
K
Furge
Kyle
K
Teh
Bin T
BT
Netto
George
G
Pili
Roberto
R
D020533:Angiogenesis Inhibitors / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004848:Epithelium / Q000187:drug effects / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008648:Mesoderm / Q000187:drug effects / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D055806:Microvessels / Q000187:drug effects; D020286:Pericytes / Q000187:drug effects / Q000473:pathology; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011758:Pyrroles / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D012878:Skin Neoplasms / Q000556:secondary; D000077210:Sunitinib; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000077210:Sunitinib