Contrasted effects of the multitarget TKi vandetanib on docetaxel-sensitive and docetaxel-resistant prostate cancer cell lines

Urol Oncol. 2013 Nov;31(8):1567-75. doi: 10.1016/j.urolonc.2012.03.003. Epub 2012 May 17.

Abstract

Objectives: Overexpression of epidermal growth factor receptor (EGFR) and angiogenic factors is associated with the progression of androgen-independent prostate cancer (AIPC). We examined the effects of vandetanib, an inhibitor of vascular endothelial growth factor (VEGFR), EGFR, and rearranged during transfection (RET) tyrosine-kinase activities, alone or combined with docetaxel, on PC3 docetaxel-sensitive (PC3wt) or docetaxel-resistant (PC3R) AIPC cell growth in vivo and in vitro.

Methods: Mice bearing PC3wt or PC3R tumors were treated for 3 weeks with vandetanib (25 or 50 mg/kg/d p.o., 5 d/wk), docetaxel (10 or 30 mg/kg i.p., 1 d/wk), or their combination (low or high doses). Xenograft tumors were analyzed for expression of Ki-67, EGFR, VEGFR2, and production of VEGFA.

Results: On PC3wt, vandetanib at both doses stimulated tumor growth, whereas docetaxel at both doses exerted strong growth-inhibiting effects. The low-dose vandetanib-docetaxel combination resulted in tumor growth similar to that of control, whereas the high-dose combination induced a significant antiproliferative effect. In contrast, on PC3R, the low-dose of vandetanib had no effect on tumor growth, whereas the high-dose of vandetanib significantly inhibited tumor growth. Docetaxel at both doses exerted moderate and transient antitumor effects. The combination of high-dose vandetanib with high-dose docetaxel resulted in antiproliferative effects, which were lower than expected from the sum of individual drug effects. Importantly, tumor analyses revealed overexpression of the EGFR/VEGFR pathways in PC3R relative to PC3wt.

Conclusion: Present results suggest that vandetanib should not be associated with docetaxel in treatment-naive or docetaxel-resistant prostate cancer (CaP). The use of high-dose vandetanib alone may warrant further investigation in patients with docetaxel-resistant AIPC overexpressing VEGFR/EGFR pathways.

Keywords: Docetaxel; Epidermal growth factor receptor (EGFR); Prostate cancer; VEGFA; VEGFR; Vandetanib.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Animals
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Docetaxel
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm / drug effects
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Humans
  • Ki-67 Antigen / metabolism
  • Male
  • Mice
  • Mice, Inbred Strains
  • Piperidines / pharmacology*
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / metabolism
  • Quinazolines / pharmacology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Taxoids / pharmacology*
  • Time Factors
  • Tumor Burden / drug effects
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / genetics
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Ki-67 Antigen
  • Piperidines
  • Protein Kinase Inhibitors
  • Quinazolines
  • Taxoids
  • Vascular Endothelial Growth Factor A
  • Docetaxel
  • ErbB Receptors
  • Protein-Tyrosine Kinases
  • Vascular Endothelial Growth Factor Receptor-2
  • vandetanib