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Kutikov A , Makhov P , Golovine K , Canter DJ , Sirohi M , Street R , Simhan J , Uzzo RG , Kolenko VM
Interleukin-6: A Potential Biomarker of Resistance to Multitargeted Receptor Tyrosine Kinase Inhibitors in Castration-resistant Prostate Cancer
Urology. 2011 Oct;78(4) :968 e7-968 e11
PMID: 21982018    PMCID: PMC3190126   
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OBJECTIVE: To determine if cellular interleukin-6 production predicts response to tyrosine kinase inhibitors (TKIs). As clinical experience using TKIs in patients with castration-resistant prostate cancer (CRPC) matures, Phase II trials show a heterogeneous response to sunitinib in CRPC patients. Change in serum prostate-specific antigen (PSA) level has proven unreliable for prediction of CRPC response to TKIs. Interleukin-6 (IL-6), a critical mediator of prostate cancer pathogenesis, has been shown to rise in patients with disease progression. As such, we investigated whether cellular IL-6 production can predict TKI response in both in vitro and in vivo models. METHODS: IL-6 mRNA levels and protein expression were examined by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Apoptosis was examined using the terminal dUTP nick-end labeling assay. For in vivo studies, a CRPC xenograft model in C.B17/Icr-scid mice was used. RESULTS: PC-3 and DU-145 CRPC cell lines exhibited a heterogeneous response to sunitinib and pazopanib. Dose-dependent reduction of IL-6 was observed in TKI-sensitive DU-145 cells. In contrast, the TKI-resistant PC-3 cells failed to suppress IL-6 secretion. Instead, in the presence of tumor necrosis factor-alpha, IL-6 rose significantly upon administration of TKIs. Findings of in vitro experiments were confirmed in an in vivo mouse model of CRPC. CONCLUSION: Sensitivity of CRPC cells to TKIs is heterogeneous. These findings are consistent with results of recently published Phase II clinical trials using sunitinib in patients with CRPC. A substantial rise in IL-6 occurs both in vitro and in vivo in the presence of TKIs in resistant PC-3 cells but not in TKI-sensitive DU-145 cells. These findings suggest that IL-6 may represent a biomarker for TKI resistance in patients with CRPC.
Kutikov, Alexander Makhov, Peter Golovine, Konstantin Canter, Daniel J Sirohi, Mohit Street, Ryan Simhan, Jay Uzzo, Robert G Kolenko, Vladimir M United States Urology Urology. 2011 Oct;78(4):968.e7-968.e11.