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

Dan Huang, Yan Ding, Ming Zhou, Brian I. Rini, David Petillo, Chao Nan Qian, Richard Kahnoski, P. Andrew Futreal, Kyle A. Furge, Bin Tean Teh

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289 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1063-1071
Number of pages9
JournalCancer research
Volume70
Issue number3
DOIs
StatePublished - Feb 1 2010

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Huang, D., Ding, Y., Zhou, M., Rini, B. I., Petillo, D., Qian, C. N., Kahnoski, R., Futreal, P. A., Furge, K. A., & Teh, B. T. (2010). Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma. Cancer research, 70(3), 1063-1071. https://doi.org/10.1158/0008-5472.CAN-09-3965