title: Effects of preset sequential administrations of sunitinib and everolimus on tumour differentiation in Caki-1 renal cell carcinoma.
abstract: BACKGROUND
  Sunitinib (VEGFR/PDGFR inhibitor) and everolimus (mTOR inhibitor) are both approved for advanced renal cell carcinoma (RCC) as first-line and second-line therapy, respectively. In the clinics, sunitinib treatment is limited by the emergence of acquired resistance, leading to a switch to second-line treatment at progression, often based on everolimus. No data have been yet generated on programmed alternating sequential strategies combining alternative use of sunitinib and everolimus before progression. Such strategy is expected to delay the emergence of acquired resistance and improve tumour control. The aim of our study was to assess the changes in tumours induced by three different sequences administration of sunitinib and everolimus.
  
  
  METHODS
  In human Caki-1 RCC xenograft model, sunitinib was alternated with everolimus every week, every 2 weeks, or every 3 weeks. Effects on necrosis, hypoxia, angiogenesis, and EMT status were assessed by immunohisochemistry and immunofluorescence.
  
  
  RESULTS
  Sunitinib and everolimus programmed sequential regimens before progression yielded longer median time to tumour progression than sunitinib and everolimus monotherapies. In each group of treatment, tumour growth control was associated with inhibition of mTOR pathway and changes from a mesenchymal towards an epithelial phenotype, with a decrease in vimentin and an increase in E-cadherin expression. The sequential combinations of these two agents in a RCC mouse clinical trial induced antiangiogenic effects, leading to tumour necrosis.
  
  
  CONCLUSIONS
  In summary, our study showed that alternate sequence of sunitinib and everolimus mitigated the development of mesenchymal phenotype compared with sunitinib as single agent.
authors.affiliation: 1] AAREC Filia Research, 1 place Paul Verlaine, 92100 Boulogne Billancourt, France [2] Inserm U728, Department of Medical Oncology, Beaujon University Hospital, 100 Boulevard du general Leclerc, 92110 Clichy, France.
authors.forename: C
authors.initials: C
authors.lastname: Dos Santos
authors.affiliation: 1] AAREC Filia Research, 1 place Paul Verlaine, 92100 Boulogne Billancourt, France [2] Inserm U728, Department of Medical Oncology, Beaujon University Hospital, 100 Boulevard du general Leclerc, 92110 Clichy, France.
authors.forename: A
authors.initials: A
authors.lastname: Tijeras-Raballand
authors.affiliation: 1] AAREC Filia Research, 1 place Paul Verlaine, 92100 Boulogne Billancourt, France [2] Inserm U728, Department of Medical Oncology, Beaujon University Hospital, 100 Boulevard du general Leclerc, 92110 Clichy, France.
authors.forename: M
authors.initials: M
authors.lastname: Serova
authors.affiliation: Inserm U728, Department of Medical Oncology, Beaujon University Hospital, 100 Boulevard du general Leclerc, 92110 Clichy, France.
authors.forename: S
authors.initials: S
authors.lastname: Sebbagh
authors.affiliation: Novartis Pharma SAS, 2 et 4 rue Lionel Terray, 92506 Rueil Malmaison, France.
authors.forename: K
authors.initials: K
authors.lastname: Slimane
authors.affiliation: New drugs Evaluation Laboratory, Center of Experimental Therapeutics and Medical Oncology, Oncology Department, CHUV, Lausanne Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Faivre
authors.affiliation: 1] AAREC Filia Research, 1 place Paul Verlaine, 92100 Boulogne Billancourt, France [2] New drugs Evaluation Laboratory, Center of Experimental Therapeutics and Medical Oncology, Oncology Department, CHUV, Lausanne Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: de Gramont
authors.affiliation: Inserm U728, Department of Medical Oncology, Beaujon University Hospital, 100 Boulevard du general Leclerc, 92110 Clichy, France.
authors.forename: E
authors.initials: E
authors.lastname: Raymond
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D004334:Drug Administration Schedule; D000068338:Everolimus; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects; D007680:Kidney Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D000077210:Sunitinib; D023041:Xenograft Model Antitumor Assays
chemical_list: D007211:Indoles; D011758:Pyrroles; D000068338:Everolimus; D000077210:Sunitinib; D020123:Sirolimus