title: Combining EGFR and mTOR blockade for the treatment of epithelioid sarcoma.
abstract: OBJECTIVE
  Molecular deregulations underlying epithelioid sarcoma (ES) progression are poorly understood yet critically needed to develop new therapies. Epidermal growth factor receptor (EGFR) is overexpressed in ES; using preclinical models, we examined the ES EGFR role and assessed anti-ES EGFR blockade effects, alone and with mTOR inhibition.
  
  
  METHODS
  EGFR and mTOR expression/activation was examined via tissue microarray (n = 27 human ES specimens; immunohistochemistry) and in human ES cell lines (Western blot and quantitative reverse transcriptase PCR). Cell proliferation, survival, migration, and invasion effects of EGFR and mTOR activation treated with erlotinib (anti-EGFR small-molecule inhibitor) alone and combined with rapamycin were assessed in cell culture assays. In vivo growth effects of erlotinib alone or with rapamycin were evaluated using severe combined immunodeficient mouse ES xenograft models.
  
  
  RESULTS
  EGFR was expressed and activated in ES specimens and cell lines. EGFR activation increased ES cell proliferation, motility, and invasion and induced cyclin D1, matrix metalloproteinase (MMP) 2, and MMP9 expression. EGFR blockade inhibited these processes and caused significant cytostatic ES growth inhibition in vivo. mTOR pathway activation at varying levels was identified in all tissue microarray-evaluable ES tissues; 88% of samples had no or reduced PTEN expression. Similarly, both ES cell lines showed enhanced mTOR activity; VAESBJ cells exhibited constitutive mTOR activation uncoupled from EGFR signaling. Most importantly, combined erlotinib/rapamycin resulted in synergistic anti-ES effects in vitro and induced superior tumor growth inhibition in vivo versus single agent administration.
  
  
  CONCLUSIONS
  EGFR and mTOR signaling pathways are deregulated in ES. Preclinical ES model-derived insights suggest that combined inhibition of these targets might be beneficial, supporting evaluations in clinical trials.
authors.affiliation: Department of Surgical Oncology, Adult Sarcoma Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Xianbiao
authors.initials: X
authors.lastname: Xie
authors.forename: Markus P H
authors.initials: MP
authors.lastname: Ghadimi
authors.forename: Eric D
authors.initials: ED
authors.lastname: Young
authors.forename: Roman
authors.initials: R
authors.lastname: Belousov
authors.forename: Quan-Sheng
authors.initials: QS
authors.lastname: Zhu
authors.forename: Juehui
authors.initials: J
authors.lastname: Liu
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Lopez
authors.forename: Chiara
authors.initials: C
authors.lastname: Colombo
authors.forename: Tingsheng
authors.initials: T
authors.lastname: Peng
authors.forename: David
authors.initials: D
authors.lastname: Reynoso
authors.forename: Jason L
authors.initials: JL
authors.lastname: Hornick
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lazar
authors.forename: Dina
authors.initials: D
authors.lastname: Lev
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D012509:Sarcoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; C546842:MTOR protein, human; D066246:ErbB Receptors; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus