title: Angiogenic and signalling proteins correlate with sensitivity to sequential treatment in renal cell cancer.
abstract: BACKGROUND
  We aimed to study key signalling proteins involved in angiogenesis and proliferation on the response to inhibitors of tyrosine kinases and mammalian target of rapamycin in first- and in second-line treatment of renal cell carcinoma (RCC).
  
  
  METHODS
  In a panel of human RCC tumours, in vitro and in nude mice, we evaluated the effect of sunitinib, sorafenib and everolimus, alone and in sequence, on tumour growth and expression of signalling proteins involved in proliferation and resistance to treatment.
  
  
  RESULTS
  We demonstrated that, as single agents, sunitinib, sorafenib and everolimus share similar activity in inhibiting cell proliferation, signal transduction and vascular endothelial growth factor (VEGF) secretion in different RCC models, both in vitro and in tumour xenografts. Pre-treatment with sunitinib reduced the response to subsequent sunitinib and sorafenib but not to everolimus. Inability by sunitinib to persistently inhibit HIF-1, VEGF and pMAPK anticipated treatment resistance in xenografted tumours. After first-line sunitinib, second-line treatment with everolimus was more effective than either sorafenib or rechallenge with sunitinib in interfering with signalling proteins, VEGF and interleukin-8, translating into a significant advantage in tumour growth inhibition and mice survival.
  
  
  CONCLUSIONS
  We demonstrated that a panel of angiogenic and signalling proteins can correlate with the onset of resistance to sunitinib and the activity of everolimus in second line.
authors.affiliation: Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica, Università di Napoli Federico II, Naples, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Rosa
authors.forename: V
authors.initials: V
authors.lastname: Damiano
authors.forename: L
authors.initials: L
authors.lastname: Nappi
authors.forename: L
authors.initials: L
authors.lastname: Formisano
authors.forename: F
authors.initials: F
authors.lastname: Massari
authors.forename: A
authors.initials: A
authors.lastname: Scarpa
authors.forename: G
authors.initials: G
authors.lastname: Martignoni
authors.forename: R
authors.initials: R
authors.lastname: Bianco
authors.forename: G
authors.initials: G
authors.lastname: Tortora
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D042501:Angiogenic Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D000068338:Everolimus; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000077157:Sorafenib; D000077210:Sunitinib; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D042501:Angiogenic Proteins; D000970:Antineoplastic Agents; D007211:Indoles; D009363:Neoplasm Proteins; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D009536:Niacinamide; D000068338:Everolimus; D000077157:Sorafenib; D011505:Protein-Tyrosine Kinases; D000077210:Sunitinib; D020123:Sirolimus