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PMID: 20103651 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma.

Cancer research ·Vol. 70 ·No. 3 ·2010-02-01 ·Pages 1063-71

Huang D, Ding Y, Zhou M, Rini BI, Petillo D, Qian CN, Kahnoski R, Futreal PA, Furge KA, Teh BT

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.

MeSH Terms
Angiogenesis Inhibitors/pharmacology Animals Antibodies, Neutralizing/pharmacology Carcinoma, Renal Cell/drug therapy,metabolism,pathology Cell Line, Tumor Drug Resistance, Neoplasm/drug effects,genetics Enzyme-Linked Immunosorbent Assay Female Gene Expression Regulation, Neoplastic Humans Indoles/pharmacology Interleukin-8/blood,immunology,metabolism Kidney Neoplasms/drug therapy,metabolism,pathology Mice Mice, Inbred BALB C Mice, Nude Pyrroles/pharmacology Sunitinib Xenograft Model Antitumor Assays
Chemicals
Angiogenesis Inhibitors Antibodies, Neutralizing Indoles Interleukin-8 Pyrroles Sunitinib
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Huang Dan
Laboratory of Cancer Genetics, Laboratory of Computational Biology, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA.
Ding Yan
Zhou Ming
Rini Brian I
Petillo David
Qian Chao-Nan
Kahnoski Richard
Futreal P Andrew
Furge Kyle A
Teh Bin Tean
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Article Info
Journal
Cancer research
Abbr.
Cancer Res
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-09-3965
Published
2010-02-01
Epub
2010-00-26
Pages
1063-71
Language
English
Region
United States
NLM ID
2984705R
PMCID
PMC3719378
Subset
IM
Grants
Wellcome Trust · 077012 · United Kingdom
Wellcome Trust · 077012/Z/05/Z · United Kingdom
External Links
PubMed source DOI: 10.1158/0008-5472.CAN-09-3965 PMC Full Text View journal details
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