KRAS(G12D)- and BRAF(V600E)-induced transformation of murine pancreatic epithelial cells requires MEK/ERK-stimulated IGF1R signaling Journal Article

   

Authors:	Appleman, V. A.; Ahronian, L. G.; Cai, J.; Klimstra, D. S.; Lewis, B. C.
Article Title:	KRAS(G12D)- and BRAF(V600E)-induced transformation of murine pancreatic epithelial cells requires MEK/ERK-stimulated IGF1R signaling
Abstract:	Mutation of KRAS is a common initiating event in pancreatic ductal adenocarcinoma (PDAC). Yet, the specific roles of KRAS-stimulated signaling pathways in the transformation of pancreatic ductal epithelial cells (PDEC), putative cells of origin for PDAC, remain unclear. Here, we show that KRAS G12D and BRAF V600E enhance PDEC proliferation and increase survival after exposure to apoptotic stimuli in a manner dependent on MEK/ERK and PI3K/AKT signaling. Interestingly, we find that activation of PI3K/AKT signaling occurs downstream of MAP-ERK kinase (MEK), and is dependent on the autocrine activation of the insulin-like growth factor (IGF) receptor (IGF1R) by IGF2. Importantly, IGF1R inhibition impairs KRAS G12D- and BRAF V600E-induced survival, whereas ectopic IGF2 expression rescues KRAS G12D- and BRAF V600E-mediated survival downstream of MEK inhibition. Moreover, we show that KRAS G12D- and BRAF V600E-induced tumor formation in an orthotopic model requires IGF1R. Interestingly, we show that while individual inhibition of MEKor IGF1R does not sensitize PDAC cells to apoptosis, their concomitant inhibition reduces survival. Our findings identify a novel mechanism of PI3K/AKT activation downstream of activated KRAS, illustrate the importance of MEK/ERK, PI3K/AKT, and IGF1R signaling in pancreatic tumor initiation, and suggest potential therapeutic strategies for this malignancy. ©2012 AACR.
Journal Title:	Molecular Cancer Research
Volume:	10
Issue:	9
ISSN:	1541-7786
Publisher:	American Association for Cancer Research
Date Published:	2012-09-01
Start Page:	1228
End Page:	1239
Language:	English
DOI:	10.1158/1541-7786.mcr-12-0340-t
PROVIDER:	scopus
PUBMED:	22871572
PMCID:	PMC3973739
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84866517360&partnerID=40&md5=9c1f92686708b8b65158809baa9cf3c2
Notes:	--- - "Export Date: 1 October 2012" - "CODEN: MCROC" - "Source: Scopus"

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