A Central role for RAF→MEK→ERK signaling in the genesis of pancreatic ductal adenocarcinoma

Eric A. Collisson, Christy L. Trejo, Jillian M. Silva, Shenda Gu, James Korkola, Laura Heiser, Roch Philippe Charles, Brian A. Rabinovich, Byron Hann, David Dankort, Paul Spellman, Wayne A. Phillips, Joe Gray, Martin McMahon

Research output: Contribution to journalArticle

135 Citations (Scopus)

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 BRAFV600E, but not PIK3CAH1047R, in the mouse pancreas leads to pancreatic intraepithelial neoplasia (PanIN) lesions. Moreover, concomitant expression of BRAFV600E and TP53R270H 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 difficult to treat, in large part, due to recurrent mutations in the KRAS gene. Here, we define 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.

Original languageEnglish (US)
Pages (from-to)685-693
Number of pages9
JournalCancer Discovery
Volume2
Issue number8
DOIs
StatePublished - Aug 2012

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Adenocarcinoma
Maintenance
Cell Line
Mutation
1-Phosphatidylinositol 4-Kinase
Mitogen-Activated Protein Kinase Kinases
Extracellular Signal-Regulated MAP Kinases
Drug Combinations
Mitogens
Dissection
Pancreas
Genes
Neoplasms
Proteins

ASJC Scopus subject areas

  • Oncology

Cite this

A Central role for RAF→MEK→ERK signaling in the genesis of pancreatic ductal adenocarcinoma. / Collisson, Eric A.; Trejo, Christy L.; Silva, Jillian M.; Gu, Shenda; Korkola, James; Heiser, Laura; Charles, Roch Philippe; Rabinovich, Brian A.; Hann, Byron; Dankort, David; Spellman, Paul; Phillips, Wayne A.; Gray, Joe; McMahon, Martin.

In: Cancer Discovery, Vol. 2, No. 8, 08.2012, p. 685-693.

Research output: Contribution to journalArticle

Collisson, EA, Trejo, CL, Silva, JM, Gu, S, Korkola, J, Heiser, L, Charles, RP, Rabinovich, BA, Hann, B, Dankort, D, Spellman, P, Phillips, WA, Gray, J & McMahon, M 2012, 'A Central role for RAF→MEK→ERK signaling in the genesis of pancreatic ductal adenocarcinoma', Cancer Discovery, vol. 2, no. 8, pp. 685-693. https://doi.org/10.1158/2159-8290.CD-11-0347
Collisson, Eric A. ; Trejo, Christy L. ; Silva, Jillian M. ; Gu, Shenda ; Korkola, James ; Heiser, Laura ; Charles, Roch Philippe ; Rabinovich, Brian A. ; Hann, Byron ; Dankort, David ; Spellman, Paul ; Phillips, Wayne A. ; Gray, Joe ; McMahon, Martin. / A Central role for RAF→MEK→ERK signaling in the genesis of pancreatic ductal adenocarcinoma. In: Cancer Discovery. 2012 ; Vol. 2, No. 8. pp. 685-693.
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