title: Metformin Treatment Does Not Inhibit Growth of Pancreatic Cancer Patient-Derived Xenografts.
abstract: There is currently tremendous interest in developing anti-cancer therapeutics targeting cell signaling pathways important for both cancer cell metabolism and growth. Several epidemiological studies have shown that diabetic patients taking metformin have a decreased incidence of pancreatic cancer. This has prompted efforts to evaluate metformin, a drug with negligible toxicity, as a therapeutic modality in pancreatic cancer. Preclinical studies in cell line xenografts and one study in patient-derived xenograft (PDX) models were promising, while recently published clinical trials showed no benefit to adding metformin to combination therapy regimens for locally advanced and metastatic pancreatic cancer. PDX models in which patient tumors are directly engrafted into immunocompromised mice have been shown to be excellent preclinical models for biomarker discovery and therapeutic development. We evaluated the response of four PDX tumor lines to metformin treatment and found that all four of our PDX lines were resistant to metformin. We found that the mechanisms of resistance may occur through lack of sustained activation of adenosine monophosphate-activated protein kinase (AMPK) or downstream reactivation of the mammalian target of rapamycin (mTOR). Moreover, combined treatment with metformin and mTOR inhibitors failed to improve responses in cell lines, which further indicates that metformin alone or in combination with mTOR inhibitors will be ineffective in patients, and that resistance to metformin may occur through multiple pathways. Further studies are required to better understand these mechanisms of resistance and inform potential combination therapies with metformin and existing or novel therapeutics.
authors.affiliation: Department of Pharmacology, School of Medicine, The University of North Carolina, Chapel Hill, NC, United States of America.|Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC, United States of America.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Lipner
authors.affiliation: Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC, United States of America.
authors.forename: Raoud
authors.initials: R
authors.lastname: Marayati
authors.affiliation: Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC, United States of America.
authors.forename: Yangmei
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC, United States of America.
authors.forename: Xianxi
authors.initials: X
authors.lastname: Wang
authors.affiliation: ProHealth Care Regional Cancer Center, Waukesha, WI, United States of America.
authors.forename: Laura
authors.initials: L
authors.lastname: Raftery
authors.affiliation: Department of Medicine, Division of Medical Oncology, University of Indiana, Indianapolis, IN, United States of America.
authors.forename: Bert H
authors.initials: BH
authors.lastname: O'Neil
authors.affiliation: Department of Pharmacology, School of Medicine, The University of North Carolina, Chapel Hill, NC, United States of America.|Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC, United States of America.|Department of Surgery, Division of Surgical Oncology and Endocrinology, The University of North Carolina, Chapel Hill, NC, United States of America.
authors.forename: Jen Jen
authors.initials: JJ
authors.lastname: Yeh
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004357:Drug Synergism; D015870:Gene Expression; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D007004:Hypoglycemic Agents; D047428:Protein Kinase Inhibitors; D008687:Metformin; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases