title: Upstream and Downstream Co-inhibition of Mitogen-Activated Protein Kinase and PI3K/Akt/mTOR Pathways in Pancreatic Ductal Adenocarcinoma.
abstract: Extensive cross talk exists between PI3K/Akt/mTOR and mitogen-activated protein kinase (MAPK) pathways, and both are upregulated in pancreatic ductal adenocarcinoma (PDAC). Our previous study suggested that epidermal growth factor receptor inhibitor erlotinib which acts upstream of these pathways acts synergistically with PI3K inhibitors in PDAC. Horizontal combined blockade upstream and downstream of these two pathways is therefore explored.
  
  
  
  Erlotinib paired with PI3K inhibitor (BYL719) was tested against erlotinib plus dual PI3K/mTOR inhibitor BEZ-235, and MEK inhibitor (PD98059) plus BEZ235, on five primary PDAC cell lines and on two pairs of parent and erlotinib-resistant (ER) cell lines. A range of in vitro assays including cell proliferation, Western blotting, migration, clonogenic, cell cycle, and apopotic assays was used to test for the efficacy of combined blockade.
  
  
  
  Dual downstream blockade of the MAPK and PAM pathways was more effective in attenuating downstream molecular signals. Synergy was demonstrated for erlotinib and BEZ235 and for PD-98059 and BEZ-235. This resulted in a trend of increased growth cell cycle arrest, apoptosis, cell proliferation, and colony and migration suppression. This combination showed more efficacy in cell lines with acquired resistance to erlotinib.
  
  
  
  The additional mTOR blockade provided by BEZ235 in combined blockade resulted in increased anticancer effect. The hypersensitivity of ER cell lines to additional mTOR blockade suggested PAM pathway oncogenic dependence via mTOR. Dual downstream combined blockade of MAPK and PAM pathways with MEK and PI3K/mTOR inhibitor appeared most effective and represents an attractive therapeutic strategy against pancreatic cancer and its associated drug resistance.
authors.affiliation: Cancer Surgery Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Sydney, NSW, Australia; Department of Medical Oncology, Gosford Hospital, Sydney, NSW, Australia.
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Wong
authors.affiliation: Cancer Surgery Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Sydney, NSW, Australia.
authors.forename: Aiqun
authors.initials: A
authors.lastname: Xue
authors.affiliation: Hormones and Cancer, Kolling Institute of Medical Research, University of Sydney, Sydney, NSW, Australia.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Baxter
authors.affiliation: Department of Medical Oncology, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia.
authors.forename: Nick
authors.initials: N
authors.lastname: Pavlakis
authors.affiliation: Cancer Surgery Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Sydney, NSW, Australia; Department of Upper Gastrointestinal Surgery, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia.
authors.forename: Ross C
authors.initials: RC
authors.lastname: Smith
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D005419:Flavonoids; D007093:Imidazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; D013844:Thiazoles; C585539:Alpelisib; D000069347:Erlotinib Hydrochloride; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; C531198:dactolisib; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one