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Data from A Central Role for RAF→MEK→ERK Signaling in the Genesis of Pancreatic Ductal Adenocarcinoma
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Data from A Central Role for RAF→MEK→ERK Signaling in the Genesis of Pancreatic Ductal Adenocarcinoma
Data from A Central Role for RAF→MEK→ERK Signaling in the Genesis of Pancreatic Ductal Adenocarcinoma
EC
Eric A. Collisson
Eric A. Collisson
CT
Christy L. Trejo
Christy L. Trejo
JS
Jillian M. Silva
Jillian M. Silva
SG
Shenda Gu
Shenda Gu
JK
James E. Korkola
James E. Korkola
LH
Laura M. Heiser
Laura M. Heiser
RC
Roch-Philippe Charles
Roch-Philippe Charles
BR
Brian A. Rabinovich
Brian A. Rabinovich
BH
Byron Hann
Byron Hann
DD
David Dankort
David Dankort
PS
Paul T. Spellman
Paul T. Spellman
WP
Wayne A. Phillips
Wayne A. Phillips
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3 April 2023
other
Published by
American Association for Cancer Research (AACR)
https://doi.org/10.1158/2159-8290.c.6545702
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. Cancer Discov; 2(8); 685–93. ©2012 AACR.Read the Commentary on this article by Hanrahan et al., p. 666.This article is highlighted in the In This Issue feature, p. 653.
Keywords
TREATMENT
PDA
PHARMACOLOGIC
EFFECTOR PATHWAY
KRAS MUTATION
RAF
ERK
MEK
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Open Access