title: Stromal cell-derived factor 1α mediates resistance to mTOR-directed therapy in pancreatic cancer.
abstract: OBJECTIVE
  The factors preventing the translation of preclinical findings supporting the clinical development mTOR-targeted therapy in pancreatic cancer therapy remain undetermined. Stromal cell.derived factor 1α (SDF-1α)-CXCR4 signaling was examined as a representative microenvironmental factor able to promote mTOR-targeted therapy resistance in pancreatic cancer.
  
  
  METHODS
  Primary pancreas explant xenografts and in vitro experiments were used to perform pharmacodynamic analyses of SDF-1α-CXCR4 regulation of the mTOR pathway. Combinatorial effects of CXCR4, EGFR, and mTOR pharmacologic inhibition were evaluated in temsirolimus-resistant and -sensitive xenografts. Intratumoral gene and protein expressions of mTOR pathway effectors cyclin D1, c-Myc, and VEGF were evaluated.
  
  
  RESULTS
  Baseline intratumoral SDF-1α gene expression correlated with temsirolimus resistance in explant models. SDF-1α stimulation of pancreatic cells resulted in CXCR4-mediated PI3-kinase-dependent S6-RP phosphorylation (pS6-RP) on exposure to temsirolimus. Combinatorial therapy with AMD3465 (CXCR4 small-molecule inhibitor) and temsirolimus resulted in effective tumor growth inhibition to overcome temsirolimus resistance. In contrast, SDF-1α exposure induced a temsirolimus-resistant phenotype in temsirolimus-sensitive explants. AMD3465 inhibited CXCR4-mediated intratumoral S6-RP phosphorylation and cyclin D and c-myc gene expression. Next, CXCR4 promoted intratumoral EGFR expression in association with temsirolimus resistance. Treatment with AMD3465, temsirolimus- and erlotinib-mediated tumor growth inhibition to overcome temsirolimus resistance in the explant model. Lastly, SDF-1α-CXCR4 signaling increased intratumoral VEGF gene and protein expression.
  
  
  CONCLUSIONS
  SDF-1α-CXCR4 signaling represents a microenvironmental factor that can maintain mTOR pathway fidelity to promote resistance to mTOR-targeted therapy in pancreatic cancer by a variety of mechanisms such as recruitment of EGFR signaling and angiogenesis.
authors.affiliation: University of Colorado Cancer Center, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA. colin.weekes@ucdenver.edu
authors.forename: Colin D
authors.initials: CD
authors.lastname: Weekes
authors.forename: Dongweon
authors.initials: D
authors.lastname: Song
authors.forename: John
authors.initials: J
authors.lastname: Arcaroli
authors.forename: Lora A
authors.initials: LA
authors.lastname: Wilson
authors.forename: Belen
authors.initials: B
authors.lastname: Rubio-Viqueira
authors.forename: George
authors.initials: G
authors.lastname: Cusatis
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Garrett-Mayer
authors.forename: Wells A
authors.initials: WA
authors.lastname: Messersmith
authors.forename: Robert A
authors.initials: RA
authors.lastname: Winn
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000378:metabolism*; D019938:Cyclin D1 / Q000096:biosynthesis; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D011725:Pyridines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D054387:Receptors, CXCR / Q000235:genetics; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014183:Transplantation, Heterologous; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: D054377:Chemokine CXCL12; D019938:Cyclin D1; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D011725:Pyridines; D011799:Quinazolines; D034741:RNA, Small Interfering; D054387:Receptors, CXCR; D019718:Receptors, CXCR4; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A; C501896:ACKR3 protein, human; C527276:CXCR4 protein, human; C489427:MYC protein, human; C503590:N-(1,4,8,11- tetraazacyclotetradecanyl-1,4-phenylenebis(methylene))-2-(aminomethyl)- pyridine; C467484:VEGFA protein, human; C401859:temsirolimus; C546842:MTOR protein, human; C512478:EGFR protein, human