title: Interleukin-6: a potential biomarker of resistance to multitargeted receptor tyrosine kinase inhibitors in castration-resistant prostate cancer.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA. alexander.kutikov@fccc.edu
authors: Alexander
authors: A
authors: Kutikov
authors: Peter
authors: P
authors: Makhov
authors: Konstantin
authors: K
authors: Golovine
authors: Daniel J
authors: DJ
authors: Canter
authors: Mohit
authors: M
authors: Sirohi
authors: Ryan
authors: R
authors: Street
authors: Jay
authors: J
authors: Simhan
authors: Robert G
authors: RG
authors: Uzzo
authors: Vladimir M
authors: VM
authors: Kolenko
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000097:blood*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007191:Indazoles; D007211:Indoles / Q000494:pharmacology; D015850:Interleukin-6 / Q000097:blood*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000097:blood*; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000494:pharmacology; D000077210:Sunitinib
chemical_list: D014408:Biomarkers, Tumor; D007191:Indazoles; D007211:Indoles; D015850:Interleukin-6; D011743:Pyrimidines; D011758:Pyrroles; D012333:RNA, Messenger; D013449:Sulfonamides; C516667:pazopanib; D020794:Receptor Protein-Tyrosine Kinases; D000077210:Sunitinib