title: PTEN deficiency mediates a reciprocal response to IGFI and mTOR inhibition.
abstract: Recent evidence implicates the insulin-like growth factor (IGF) pathway in development of Ewing sarcoma, a highly malignant bone and soft-tissue tumor that primarily affects children and young adults. Despite promising results from preclinical studies of therapies that target this pathway, early-phase clinical trials have shown that a significant fraction of patients do not benefit, suggesting that cellular factors determine tumor sensitivity. Using FAIRE-seq, a chromosomal deletion of the PTEN locus in a Ewing sarcoma cell line was identified. In primary tumors, PTEN deficiency was observed in a large subset of cases, although not mediated by large chromosomal deletions. PTEN loss resulted in hyperactivation of the AKT signaling pathway. PTEN rescue led to decreased proliferation, inhibition of colony formation, and increased apoptosis. Strikingly, PTEN loss decreased sensitivity to IGF1R inhibitors but increased responsiveness to temsirolimus, a potent mTOR inhibitor, as marked by induction of autophagy. These results suggest that PTEN is lost in a significant fraction of primary tumors, and this deficiency may have therapeutic consequences by concurrently attenuating responsiveness to IGF1R inhibition while increasing activity of mTOR inhibitors. The identification of PTEN status in the tumors of patients with recurrent disease could help guide the selection of therapies.
  
  
  CONCLUSIONS
  PTEN status in Ewing sarcoma affects cellular responses to IGFI and mTOR-directed therapy, thus justifying its consideration as a biomarker in future clinical trials.
authors.affiliation: Department of Genetics and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Mukund
authors.initials: M
authors.lastname: Patel
authors.affiliation: Department of Genetics and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Gomez
authors.affiliation: Department of Genetics and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: McFadden
authors.affiliation: Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Billie M
authors.initials: BM
authors.lastname: Moats-Staats
authors.affiliation: Department of Genetics and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Sam
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Genetics and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Andres
authors.initials: A
authors.lastname: Rojas
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Travis
authors.initials: T
authors.lastname: Sapp
authors.affiliation: Department of Genetics and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Simon
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Scott V
authors.initials: SV
authors.lastname: Smith
authors.affiliation: Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Kaiser-Rogers
authors.affiliation: Department of Genetics and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. ijdavis@email.unc.edu.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Davis
mesh_terms: D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D017353:Gene Deletion; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000201:enzymology / Q000473:pathology; D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C401859:temsirolimus; D007334:Insulin-Like Growth Factor I; C546842:MTOR protein, human; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D020123:Sirolimus