title: MEK inhibition abrogates sunitinib resistance in a renal cell carcinoma patient-derived xenograft model.
abstract: Renal cell carcinoma (RCC) patients treated with tyrosine kinase inhibitors (TKI) typically respond initially, but usually develop resistance to therapy. We utilised transcriptome analysis to identify gene expression changes during development of sunitinib resistance in a RCC patient-derived xenograft (PDX) model.
  
  
  
  RCC tumours were harvested during pre-treatment, response and escape phases. Direct anti-proliferative effects of sunitinib plus MEK inhibitor were assessed. Activation status (phosphorylation) of MEK1/2 and ERK1/2 was determined, myeloid-derived suppressor cells (MDSC) sub-fractions were quantitated and G-CSF was measured by ELISA.
  
  
  
  During the response phase, tumours exhibited 91% reduction in volume, characterised by decreased expression of cell survival genes. After 4-week treatment, tumours developed resistance to sunitinib, associated with increased expression of pro-angiogenic and cell survival genes. During tumour escape, cellular movement, inflammatory response and immune cell trafficking genes were induced, along with intra-tumoural accumulation of MDSC. In this PDX model, either continuous treatment with sunitinib plus MEK inhibitor PD-0325901, or switching from sunitinib to PD-0325901 was effective. The combination of PD-0325901 with TKI suppressed intra-tumoural phospho-MEK1/2, phospho-ERK1/2 and MDSC.
  
  
  
  Continuous treatment with sunitinib alone did not maintain anti-tumour response; addition of MEK inhibitor abrogated resistance, leading to improved anti-tumour efficacy.
authors: Department of Immunology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue R40, Cleveland, OH 44195, USA.
authors: C Marcela
authors: CM
authors: Diaz-Montero
authors: Department of Immunology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue R40, Cleveland, OH 44195, USA.|Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, 9500 Euclid Avenue R40, Cleveland, OH 44195, USA.
authors: Frances J
authors: FJ
authors: Mao
authors: Quantitative Health Sciences Department, Cleveland Clinic, 9500 Euclid Avenue R40, Cleveland, OH 44195, USA.
authors: John
authors: J
authors: Barnard
authors: Department of Translational Hematology and Oncology Research, Cleveland Clinic Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue R40, Cleveland, OH 44195, USA.
authors: Yvonne
authors: Y
authors: Parker
authors: Department of Cellular and Molecular Medicine and Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, 9500 Euclid Avenue R40, Cleveland, OH 44195, USA.
authors: Maryam
authors: M
authors: Zamanian-Daryoush
authors: Case Comprehensive Cancer Center, Case Western Reserve University Medical School, Cleveland Clinic, 9500 Euclid Avenue R40, Cleveland, OH 44195, USA.
authors: John J
authors: JJ
authors: Pink
authors: Department of Immunology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue R40, Cleveland, OH 44195, USA.
authors: James H
authors: JH
authors: Finke
authors: Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue R40, Cleveland, OH 44195, USA.
authors: Brian I
authors: BI
authors: Rini
authors: Department of Translational Hematology and Oncology Research, Cleveland Clinic Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue R40, Cleveland, OH 44195, USA.
authors: Daniel J
authors: DJ
authors: Lindner
mesh_terms: D000328:Adult; D000818:Animals; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D004159:Diphenylamine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D000072737:Myeloid-Derived Suppressor Cells / Q000187:drug effects / Q000276:immunology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D015375:Receptors, Interleukin-2 / Q000172:deficiency; D000077210:Sunitinib; D047368:Tumor Burden / Q000187:drug effects; D019139:Tumor Escape / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D001549:Benzamides; D007211:Indoles; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D015375:Receptors, Interleukin-2; C506614:mirdametinib; D004159:Diphenylamine; D020929:Mitogen-Activated Protein Kinase Kinases; D000077210:Sunitinib