title: A central role for RAF→MEK→ERK signaling in the genesis of pancreatic ductal adenocarcinoma.
abstract: KRAS mutation is a hallmark of pancreatic ductal adenocarcinoma (PDA) but remains an intractable pharmacologic target. Consequently, defining RAS effector pathway(s) required for PDA initiation and maintenance is critical to improve treatment of this disease. Here, we show that expression of BRAF(V600E), but not PIK3CA(H1047R), in the mouse pancreas leads to pancreatic intraepithelial neoplasia (PanIN) lesions. Moreover, concomitant expression of BRAF(V600E) and TP53(R270H) result in lethal PDA. We tested pharmacologic inhibitors of RAS effectors against multiple human PDA cell lines. Mitogen-activated protein (MAP)/extracellular signal-regulated (ERK) kinase (MEK) inhibition was highly effective both in vivo and in vitro and was synergistic with AKT inhibition in most cell lines tested. We show that RAF→MEK→ERK signaling is central to the initiation and maintenance of PDA and to rational combination strategies in this disease. These results emphasize the value of leveraging multiple complementary experimental systems to prioritize pathways for effective intervention strategies in PDA.
  
  
  CONCLUSIONS
  PDA is diffi cult to treat, in large part, due to recurrent mutations in the KRAS gene. Here, we defi ne rational treatment approaches for the disease achievable today with existing drug combinations by thorough genetic and pharmacologic dissection of the major KRAS effector pathways, RAF→MEK→ERK and phosphoinositide 3′-kinase (PI3'K)→AKT.
authors.affiliation: Department of Medicine, Division of Hematology and Oncology, University of California, San Francisco, California, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Collisson
authors.forename: Christy L
authors.initials: CL
authors.lastname: Trejo
authors.forename: Jillian M
authors.initials: JM
authors.lastname: Silva
authors.forename: Shenda
authors.initials: S
authors.lastname: Gu
authors.forename: James E
authors.initials: JE
authors.lastname: Korkola
authors.forename: Laura M
authors.initials: LM
authors.lastname: Heiser
authors.forename: Roch-Philippe
authors.initials: RP
authors.lastname: Charles
authors.forename: Brian A
authors.initials: BA
authors.lastname: Rabinovich
authors.forename: Byron
authors.initials: B
authors.lastname: Hann
authors.forename: David
authors.initials: D
authors.lastname: Dankort
authors.forename: Paul T
authors.initials: PT
authors.lastname: Spellman
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Phillips
authors.forename: Joe W
authors.initials: JW
authors.lastname: Gray
authors.forename: Martin
authors.initials: M
authors.lastname: McMahon
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology* / Q000235:genetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D011905:Genes, ras; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases