RGD Reference Report - A central role for RAF¿MEK¿ERK signaling in the genesis of pancreatic ductal adenocarcinoma. - Rat Genome Database

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A central role for RAF¿MEK¿ERK signaling in the genesis of pancreatic ductal adenocarcinoma.

Authors: Collisson, Eric A  Trejo, Christy L  Silva, Jillian M  Gu, Shenda  Korkola, James E  Heiser, Laura M  Charles, Roch-Philippe  Rabinovich, Brian A  Hann, Byron  Dankort, David  Spellman, Paul T  Phillips, Wayne A  Gray, Joe W  McMahon, Martin 
Citation: Collisson EA, etal., Cancer Discov. 2012 Aug;2(8):685-93. doi: 10.1158/2159-8290.CD-11-0347. Epub 2012 May 24.
RGD ID: 13462040
Pubmed: PMID:22628411   (View Abstract at PubMed)
PMCID: PMC3425446   (View Article at PubMed Central)
DOI: DOI:10.1158/2159-8290.CD-11-0347   (Journal Full-text)


UNLABELLED: 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.
SIGNIFICANCE: 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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
pancreatic cancer  ISOBraf (Mus musculus)13462040; 13462040 RGD 
pancreatic cancer  IMP 13462040 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Braf  (B-Raf proto-oncogene, serine/threonine kinase)

Genes (Mus musculus)
Braf  (Braf transforming gene)

Genes (Homo sapiens)
BRAF  (B-Raf proto-oncogene, serine/threonine kinase)


Additional Information