title: Functional profiling of receptor tyrosine kinases and downstream signaling in human chondrosarcomas identifies pathways for rational targeted therapy.
abstract: OBJECTIVE
  Chondrosarcomas are notoriously resistant to cytotoxic chemotherapeutic agents. We sought to identify critical signaling pathways that contribute to their survival and proliferation, and which may provide potential targets for rational therapeutic interventions.
  
  
  METHODS
  Activation of receptor tyrosine kinases (RTK) was surveyed using phospho-RTK arrays. S6 phosphorylation and NRAS mutational status were examined in chondrosarcoma primary tumor tissues. siRNA or small-molecule inhibitors against RTKs or downstream signaling proteins were applied to chondrosarcoma cells and changes in biochemical signaling, cell cycle, and cell viability were determined. In vivo antitumor activity of BEZ235, a phosphoinositide 3-kinase (PI3K)/mTOR inhibitor, was evaluated in a chondrosarcoma xenograft model.
  
  
  RESULTS
  Several RTKs were identified as critical mediators of cell growth, but the RTK dependencies varied among cell lines. In exploration of downstream signaling pathways, strong S6 phosphorylation was found in 69% of conventional chondrosarcomas and 44% of dedifferentiated chondrosarcomas. Treatment with BEZ235 resulted in dramatic reduction in the growth of all chondrosarcoma cell lines. Tumor growth was similarly inhibited in a xenograft model of chondrosarcoma. In addition, chondrosarcoma cells with an NRAS mutation were sensitive to treatment with a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) inhibitor. Functional NRAS mutations were found in 12% of conventional central chondrosarcomas.
  
  
  CONCLUSIONS
  RTKs are commonly activated in chondrosarcoma, but because of their considerable heterogeneity, targeted inhibition of the PI3K/mTOR pathway represents a rational therapeutic strategy. Chondrosarcomas with NRAS mutations may benefit from treatment with MEK inhibitors.
authors.affiliation: Ludwig Center at Dana-Farber/Harvard and Center for Sarcoma and Bone Oncology, Department of Medical Oncology, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Yi-Xiang
authors.initials: YX
authors.lastname: Zhang
authors.forename: Jolieke G
authors.initials: JG
authors.lastname: van Oosterwijk
authors.forename: Ewa
authors.initials: E
authors.lastname: Sicinska
authors.forename: Samuel
authors.initials: S
authors.lastname: Moss
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Remillard
authors.forename: Tom
authors.initials: T
authors.lastname: van Wezel
authors.forename: Claudia
authors.initials: C
authors.lastname: Bühnemann
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Hassan
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
authors.forename: Judith V M G
authors.initials: JV
authors.lastname: Bovée
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Wagner
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D045744:Cell Line, Tumor; D002813:Chondrosarcoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D004789:Enzyme Activation; D025461:Feedback, Physiological; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D056726:Genetic Association Studies; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D020125:Mutation, Missense; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D046888:Tissue Array Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D020558:GTP Phosphohydrolases; D007093:Imidazoles; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011804:Quinolines; D020794:Receptor Protein-Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C579846:NRAS protein, human; C531198:dactolisib