Journal article
A Central role for RAF→MEK→ERK signaling in the genesis of pancreatic ductal adenocarcinoma
EA Collisson, CL Trejo, JM Silva, S Gu, JE Korkola, LM Heiser, RP Charles, BA Rabinovich, B Hann, D Dankort, PT Spellman, WA Phillips, JW Gray, M McMahon
Cancer Discovery | AMER ASSOC CANCER RESEARCH | Published : 2012
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 bo..
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Awarded by National Cancer Institute
Funding Acknowledgements
J.W. Gray has commercial research grants from GlaxoSmithKline, Pfizer, and Susan G. Komen for the Cure and is a consultant/advisory board member for New Leaf Ventures, Agendia, and KromaTiD. M. McMahon has a commercial research grant from the National Comprehensive Cancer Network. No potential conflicts of interest were disclosed by the other authors. A. Collisson is supported by NIH/NCI CA137153. Funds were provided by the Noren Fund for Pancreatic Cancer Research (to M. McMahon). W. A. Phillips is supported by project grants from the National Health and Medical Research Council of Australia. This research was supported by NIH/NCI Grants P50 CA 58207, U54 CA 112970, and NHGRI U24 CA 126551; by the Department of the Army, Award W81XWH-07-1-0663, to J.W. Gray. Funds were provided by the Noren and Hasbun Funds for Pancreatic Cancer Research, and NIH/NCI R01 CA121361 to M. McMahon.