title: Targeting Focal Adhesion Kinase and Resistance to mTOR Inhibition in Pancreatic Neuroendocrine Tumors.
abstract: BACKGROUND
  Focal adhesion kinase (FAK) mediates survival of normal pancreatic islets through activation of AKT. Upon malignant transformation of islet cells into pancreatic neuroendocrine tumors (PanNETs), AKT is frequently overexpressed and mutations in the AKT/mTOR pathway are detected. Because mTOR inhibitors rarely induce PanNET tumor regression, partly because of feedback activation of AKT, novel combination strategies are needed to target FAK/AKT/mTOR signaling.
  
  
  METHODS
  We characterized the activation of FAK in PanNETs using immunohistochemistry and Western blot analysis and tested the FAK inhibitor PF-04554878 in human PanNET cells in vitro and in vivo (at least three mice per group). In addition, we evaluated the effect of combined FAK and mTOR inhibition on PanNET viability and apoptosis. All statistical tests were two-sided.
  
  
  RESULTS
  We found that FAK is overexpressed and hyperphosphorylated in human PanNETs and that PF-04554878 strongly inhibited FAK (Tyr397) autophosphorylation in a dose-dependent manner. We found that PF-04554878 inhibited cell proliferation and clonogenicity and induced apoptosis in PanNET cells. Moreover, oral administration of PF-04554878 statistically significantly reduced tumor growth in a patient-derived xenograft model of PanNET (P = .02) and in a human PanNET xenograft model of peritoneal carcinomatosis (P = .03). Importantly, PF-04554878 synergized with the mTOR inhibitor everolimus by preventing feedback AKT activation.
  
  
  CONCLUSIONS
  We demonstrate for the first time that FAK is overexpressed in PanNETs and that inhibition of FAK activity induces apoptosis and inhibits PanNET proliferation. We found that the novel FAK inhibitor PF-04554878 synergizes with everolimus, a US Food and Drug Administration-approved agent for PanNETs. Our findings warrant the clinical investigation of combined FAK and mTOR inhibition in PanNETs.
authors.affiliation: Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL (RAF, KM, AN, MZK); Department of Medicine, University of Florida College of Medicine, Gainesville, FL (FJK); Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY (SNH).
authors.forename: Rony A
authors.initials: RA
authors.lastname: François
authors.affiliation: Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL (RAF, KM, AN, MZK); Department of Medicine, University of Florida College of Medicine, Gainesville, FL (FJK); Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY (SNH).
authors.forename: Kyungah
authors.initials: K
authors.lastname: Maeng
authors.affiliation: Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL (RAF, KM, AN, MZK); Department of Medicine, University of Florida College of Medicine, Gainesville, FL (FJK); Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY (SNH).
authors.forename: Akbar
authors.initials: A
authors.lastname: Nawab
authors.affiliation: Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL (RAF, KM, AN, MZK); Department of Medicine, University of Florida College of Medicine, Gainesville, FL (FJK); Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY (SNH).
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: Kaye
authors.affiliation: Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL (RAF, KM, AN, MZK); Department of Medicine, University of Florida College of Medicine, Gainesville, FL (FJK); Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY (SNH).
authors.forename: Steven N
authors.initials: SN
authors.lastname: Hochwald
authors.affiliation: Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL (RAF, KM, AN, MZK); Department of Medicine, University of Florida College of Medicine, Gainesville, FL (FJK); Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY (SNH).
authors.forename: Maria
authors.initials: M
authors.lastname: Zajac-Kaye
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D002277:Carcinoma / Q000188:drug therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D000068338:Everolimus; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy / Q000379:methods*; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000378:metabolism; D009930:Organic Chemicals / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010534:Peritoneal Neoplasms / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011719:Pyrazines; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D013449:Sulfonamides; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D009930:Organic Chemicals; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D013449:Sulfonamides; C584510:defactinib; D000068338:Everolimus; C546842:MTOR protein, human; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus