title: Tyrosine Kinase Signaling in Clear Cell and Papillary Renal Cell Carcinoma Revealed by Mass Spectrometry-Based Phosphotyrosine Proteomics.
abstract: OBJECTIVE
  Targeted therapies in renal cell carcinoma (RCC) are limited by acquired resistance. Novel therapeutic targets are needed to combat resistance and, ideally, target the unique biology of RCC subtypes.
  
  
  METHODS
  Tyrosine kinases provide critical oncogenic signaling and their inhibition has significantly impacted cancer care. To describe a landscape of tyrosine kinase activity in RCC that could inform novel therapeutic strategies, we performed a mass spectrometry-based system-wide survey of tyrosine phosphorylation in 10 RCC cell lines as well as 15 clear cell and 15 papillary RCC human tumors. To prioritize identified tyrosine kinases for further analysis, a 63 tyrosine kinase inhibitor (TKI) drug screen was performed.
  
  
  RESULTS
  Among the cell lines, 28 unique tyrosine phosphosites were identified across 19 kinases and phosphatases including EGFR, MET, JAK2, and FAK in nearly all samples. Multiple FAK TKIs decreased cell viability by at least 50% and inhibited RCC cell line adhesion, invasion, and proliferation. Among the tumors, 49 unique tyrosine phosphosites were identified across 44 kinases and phosphatases. FAK pY576/7 was found in all tumors and many cell lines, whereas DDR1 pY792/6 was preferentially enriched in the papillary RCC tumors. Both tyrosine kinases are capable of transmitting signals from the extracellular matrix and emerged as novel RCC therapeutic targets.
  
  
  CONCLUSIONS
  Tyrosine kinase profiling informs novel therapeutic strategies in RCC and highlights the unique biology among kidney cancer subtypes. Clin Cancer Res; 22(22); 5605-16. ©2016 AACR.
authors.affiliation: Division of Hematology & Medical Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. scott.m.haake@vanderbilt.edu eric.haura@moffitt.org.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Haake
authors.affiliation: Department of Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.
authors.forename: Jiannong
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.
authors.forename: Yun
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Department of Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.
authors.forename: Fumi
authors.initials: F
authors.lastname: Kinose
authors.affiliation: Proteomics Core Facility, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.
authors.forename: Bin
authors.initials: B
authors.lastname: Fang
authors.affiliation: Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Welsh
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.|Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee.|Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee.|Division of Nephrology, Department of Medicine, Veterans Affairs Hospital, Tennessee Valley Healthcare System, Nashville, Tennessee.
authors.forename: Roy
authors.initials: R
authors.lastname: Zent
authors.affiliation: Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Jasreman
authors.initials: J
authors.lastname: Dhillon
authors.affiliation: Genitourinary Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.
authors.forename: Julio M
authors.initials: JM
authors.lastname: Pow-Sang
authors.affiliation: Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Y Ann
authors.initials: YA
authors.lastname: Chen
authors.affiliation: Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.|Molecular Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.
authors.forename: John M
authors.initials: JM
authors.lastname: Koomen
authors.affiliation: Division of Hematology & Medical Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: W Kimryn
authors.initials: WK
authors.lastname: Rathmell
authors.affiliation: Genitourinary Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.
authors.forename: Mayer
authors.initials: M
authors.lastname: Fishman
authors.affiliation: Department of Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida. scott.m.haake@vanderbilt.edu eric.haura@moffitt.org.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Haura
mesh_terms: D002291:Carcinoma, Papillary / Q000188:drug therapy / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D013058:Mass Spectrometry / Q000379:methods; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D040901:Proteomics / Q000379:methods; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D019000:Phosphotyrosine; D014443:Tyrosine; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases