Abstract B103: KRASG12D- and BRAFV600E-induced transformation of murine pancreatic epithelial cells requires MEK/ERK-stimulated IGF1R signaling
| Autor: | David S. Klimstra, Victoria Appleman, Leanne G. Ahronian, Brian C. Lewis, JiuFeng Cai |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
MAPK/ERK pathway
medicine.medical_specialty endocrine system diseases Biology medicine.disease medicine.disease_cause digestive system diseases Endocrinology Internal medicine Pancreatic cancer medicine Cancer research KRAS Signal transduction Autocrine signalling Protein kinase B PI3K/AKT/mTOR pathway Insulin-like growth factor 1 receptor |
| Zdroj: | Tumor Biology. |
| DOI: | 10.1158/1538-7445.panca2012-b103 |
| Popis: | 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 (PDECs), putative cells of origin for PDAC, remain unclear. We therefore sought to ascertain the roles of the PI3K/AKT and MEK/ERK signaling cascades in this process. We found that KRAS G12D and an activated form of the downstream effector BRAF, 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 found that the expression of the insulin-like growth factors IGF1 and IGF2 is induced downstream of the MEK/ERK pathway, and that activation of PI3K/AKT signaling occurs downstream of MEK, and is dependent on the autocrine activation of the IGF receptor IGF1R. 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, but not PI3K inhibition. Consistent with a critical role for IGF1R in pancreatic tumorigenesis, we demonstrate that KRAS G12D - and BRAF V600E -induced tumor formation in an orthotopic model requires IGF1R. Intriguingly, we show that while individual inhibition of MEK or IGF1R does not sensitize PDAC cells to apoptosis, their concomitant inhibition reduces survival after apoptotic challenge. Our findings identify a novel mechanism of PI3K/AKT activation downstream of activated KRAS in pancreatic epithelial cells, illustrate the importance of MEK/ERK, PI3K/AKT, and IGF1R signaling in pancreatic tumor initiation, and suggest potential therapeutic strategies for this malignancy. Citation Format: Victoria Appleman, Leanne Ahronian, JiuFeng Cai, David Klimstra, Brian Lewis. KRASG12D- and BRAFV600E-induced transformation of murine pancreatic epithelial cells requires MEK/ERK-stimulated IGF1R signaling. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr B103. |
| Databáze: | OpenAIRE |
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