title: Activation of the mTOR Pathway by Oxaliplatin in the Treatment of Colorectal Cancer Liver Metastasis.
abstract: BACKGROUND
  Standard of care treatment for colorectal cancer liver metastasis consists of a cytotoxic chemotherapy in combination with a targeted agent. Clinical trials have guided the use of these combinatory therapies, but it remains unclear what the optimal combinations of cytotoxic chemotherapy with a targeted agent are.
  
  
  METHODS
  Using a genomic based approach, gene expression profiling was obtained from tumor samples of patient with colorectal cancer liver metastasis who received an oxaliplatin based therapy. Early passaged colorectal cancer liver metastasis cell lines and patient derived xenografts of colorectal cancer liver metastasis were then treated with oxaliplatin and a mTOR inhibitor.
  
  
  RESULTS
  Gene set enrichment analysis revealed that the mTOR pathway was activated in patients receiving oxaliplatin based therapy. Treatment of early passaged colorectal cancer lines and patient derived xenografts with oxaliplatin resulted in activation of the mTOR pathway. Combination therapy with oxaliplatin and a mTOR inhibitor resulted in a synergistic effect both in vitro and in vivo.
  
  
  CONCLUSIONS
  Our findings suggest a genomic based approach can be used to identify optimal combinations of cytotoxic chemotherapy with a targeted agent and that these observations can be validated both in vitro and in vivo using patient derived colorectal cancer cell lines and patient derived xenografts prior to clinical use.
authors.affiliation: Department of Medical Oncology, Duke University Medical Center, Durham, North Carolina, United States of America.|Center for Genomics and Computational Biology, Duke University, Durham, North Carolina, United States of America.
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.affiliation: Department of Medical Oncology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Amelia S
authors.initials: AS
authors.lastname: Zessin
authors.affiliation: Department of Medical Oncology, Duke University Medical Center, Durham, North Carolina, United States of America.|Center for Genomics and Computational Biology, Duke University, Durham, North Carolina, United States of America.
authors.forename: Wayne
authors.initials: W
authors.lastname: Glover
authors.affiliation: Department of Medical Oncology, Duke University Medical Center, Durham, North Carolina, United States of America.|Center for Genomics and Computational Biology, Duke University, Durham, North Carolina, United States of America.
authors.forename: David S
authors.identifier: http://orcid.org/0000-0002-8149-7180
authors.initials: DS
authors.lastname: Hsu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020128:Inhibitory Concentration 50; D008113:Liver Neoplasms / Q000209:etiology* / Q000378:metabolism* / Q000628:therapy; D008297:Male; D051379:Mice; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D059467:Transcriptome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D058570:TOR Serine-Threonine Kinases