title: Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma.
abstract: 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.
authors.affiliation: Laboratory of Cancer Genetics, Laboratory of Computational Biology, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Huang
authors.forename: Yan
authors.initials: Y
authors.lastname: Ding
authors.forename: Ming
authors.initials: M
authors.lastname: Zhou
authors.forename: Brian I
authors.initials: BI
authors.lastname: Rini
authors.forename: David
authors.initials: D
authors.lastname: Petillo
authors.forename: Chao-Nan
authors.initials: CN
authors.lastname: Qian
authors.forename: Richard
authors.initials: R
authors.lastname: Kahnoski
authors.forename: P Andrew
authors.initials: PA
authors.lastname: Futreal
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Furge
authors.forename: Bin Tean
authors.initials: BT
authors.lastname: Teh
mesh_terms: 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
chemical_list: D020533:Angiogenesis Inhibitors; D057134:Antibodies, Neutralizing; D007211:Indoles; D016209:Interleukin-8; D011758:Pyrroles; D000077210:Sunitinib