title: Phosphorylated mammalian target of rapamycin expression is associated with the response to chemoradiotherapy in patients with esophageal squamous cell carcinoma.
abstract: OBJECTIVE
  The mammalian target of rapamycin signaling pathway has been implicated in therapeutic resistance in several types of cancer. However, the significance of mammalian target of rapamycin activation in chemoradiotherapy sensitivity and its effect on the prognosis of esophageal squamous cell carcinoma treated with chemoradiotherapy remain unknown. However, this pathway is of particular interest because an effective inhibitor is available.
  
  
  METHODS
  By using immunohistochemistry, phosphorylated mammalian target of rapamycin expression was examined in 77 patients with esophageal squamous cell carcinoma treated with preoperative chemoradiotherapy followed by surgery between 1999 and 2009, and correlated with treatment outcome. With the use of CE81T/VGH and TE2 cell lines, cells were treated with chemotherapy, temsirolimus (mammalian target of rapamycin inhibitor), or a combination of chemotherapy and temsirolimus, and investigated by 3-(4.5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.
  
  
  RESULTS
  Pathologic complete response rates were 42% and 16% in patients with negative and positive phosphorylated mammalian target of rapamycin expression, respectively (P = .01). The 3-year overall survivals were 57% and 30% in patients with negative and positive phosphorylated mammalian target of rapamycin expression, respectively (P = .005). Positive phosphorylated mammalian target of rapamycin expression was independently associated with inferior overall and disease-free survival. In patients who did not achieve pathologic complete response, postchemoradiotherapy esophagectomy specimens showed significantly higher phosphorylated mammalian target of rapamycin expression than pretreatment biopsy specimens. In cell lines, concomitant administration of temsirolimus enhanced the effect of chemotherapy.
  
  
  CONCLUSIONS
  Phosphorylated mammalian target of rapamycin expression is independently associated with the response to chemoradiotherapy and prognosis of patients with esophageal squamous cell carcinoma treated with preoperative chemoradiotherapy. Mammalian target of rapamycin inhibition can sensitize esophageal cancer cells to chemotherapy. Our results suggest the potential for mammalian target of rapamycin as a therapeutic target for patients with esophageal squamous cell carcinoma who receive multimodality treatment.
authors: Department of Hematology-Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC.
authors: Shau-Hsuan
authors: SH
authors: Li
authors: Eng-Yen
authors: EY
authors: Huang
authors: Hung-I
authors: HI
authors: Lu
authors: Wan-Ting
authors: WT
authors: Huang
authors: Chueh-Chuan
authors: CC
authors: Yen
authors: Wen-Chien
authors: WC
authors: Huang
authors: Chang-Han
authors: CH
authors: Chen
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001706:Biopsy; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D059186:Chemoradiotherapy, Adjuvant; D016009:Chi-Square Distribution; D018572:Disease-Free Survival; D004938:Esophageal Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D016629:Esophagectomy; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020360:Neoadjuvant Therapy; D016017:Odds Ratio; D010766:Phosphorylation; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; C401859:temsirolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus