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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Sunitinib is a first-line treatment for advanced clear cell renal cell carcinoma (ccRCC).
• Most patients develop resistance to sunitinib within a year, leading to disease progression.
• Understanding resistance mechanisms is crucial for developing effective therapeutic strategies.

Purpose of the Study:

• To investigate the mechanisms underlying sunitinib resistance in ccRCC.
• To identify potential therapeutic targets to overcome sunitinib resistance.
• To evaluate the role of interleukin-8 (IL-8) in ccRCC sunitinib resistance.

Main Methods:

• Generation of xenograft models mimicking clinical sunitinib resistance.
• Assessment of microvessel density in sunitinib-resistant tumors.
• Measurement of IL-8 secretion in tumors and plasma.
• Evaluation of IL-8 neutralizing antibody in combination with sunitinib.
• Analysis of IL-8 expression in ccRCC tumors from patients refractory to sunitinib.

Main Results:

• Sunitinib-resistant tumors exhibited higher microvessel density, indicating escape from antiangiogenesis.
• Increased IL-8 secretion from tumors into plasma correlated with resistance.
• Coadministration of an IL-8 neutralizing antibody resensitized tumors to sunitinib.
• Elevated IL-8 expression was observed in ccRCC tumors of sunitinib-refractory patients.

Conclusions:

• Interleukin-8 (IL-8) significantly contributes to sunitinib resistance in ccRCC.
• IL-8 is a potential therapeutic target to reverse acquired or intrinsic resistance to sunitinib.
• IL-8 levels may serve as a predictive biomarker for clinical response to sunitinib treatment.