Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma.
The broad spectrum kinase inhibitor sunitinib is a first-line therapy for advanced clear cell renal cell carcinoma (ccRCC), a deadly form of kidney cancer. Unfortunately, most patients develop sunitinib resistance and progressive disease after about 1 year of treatment. In this study, we evaluated the mechanisms of resistance to sunitinib to identify the potential tactics to overcome it. Xenograft models were generated that mimicked clinical resistance to sunitinib. Higher microvessel density was found in sunitinib-resistant tumors, indicating that an escape from antiangiogenesis occurred. Notably, escape coincided with increased secretion of interleukin-8 (IL-8) from tumors into the plasma, and coadministration of an IL-8 neutralizing antibody resensitized tumors to sunitinib treatment. In patients who were refractory to sunitinib treatment, IL-8 expression was elevated in ccRCC tumors, supporting the concept that IL-8 levels might predict clinical response to sunitinib. Our results reveal IL-8 as an important contributor to sunitinib resistance in ccRCC and a candidate therapeutic target to reverse acquired or intrinsic resistance to sunitinib in this malignancy.
Huang
Dan
D
Laboratory of Cancer Genetics, Laboratory of Computational Biology, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA.
Ding
Yan
Y
Zhou
Ming
M
Rini
Brian I
BI
Petillo
David
D
Qian
Chao-Nan
CN
Kahnoski
Richard
R
Futreal
P Andrew
PA
Furge
Kyle A
KA
Teh
Bin Tean
BT
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D016209:Interleukin-8 / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011758:Pyrroles / Q000494:pharmacology*; D000077210:Sunitinib; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D057134:Antibodies, Neutralizing; D007211:Indoles; D016209:Interleukin-8; D011758:Pyrroles; D000077210:Sunitinib