Low-Dose Vertical Inhibition of the RAF-MEK-ERK Cascade Causes Apoptotic Death of KRAS Mutant Cancers

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Ozkan-Dagliyan , I , Diehl , J N , George , S D , Schaefer , A , Papke , B , Klotz-Noack , K , Waters , A M , Goodwin , C M , Gautam , P , Pierobon , M , Peng , S , Gilbert , T S K , Lin , K H , Dagliyan , O , Wennerberg , K , Petricoin , E F , Tran , N L , Bhagwat , S , Tiu , R , Peng , S-B , Herring , L E , Graves , L M , Sers , C , Wood , K C , Cox , A D & Der , C J 2020 , ' Low-Dose Vertical Inhibition of the RAF-MEK-ERK Cascade Causes Apoptotic Death of KRAS Mutant Cancers ' , Cell Reports , vol. 31 , no. 11 , 107764 . https://doi.org/10.1016/j.celrep.2020.107764

Title: Low-Dose Vertical Inhibition of the RAF-MEK-ERK Cascade Causes Apoptotic Death of KRAS Mutant Cancers
Author: Ozkan-Dagliyan, Irem; Diehl, J. Nathaniel; George, Samuel D.; Schaefer, Antje; Papke, Bjoern; Klotz-Noack, Kathleen; Waters, Andrew M.; Goodwin, Craig M.; Gautam, Prson; Pierobon, Mariaelena; Peng, Sen; Gilbert, Thomas S. K.; Lin, Kevin H.; Dagliyan, Onur; Wennerberg, Krister; Petricoin, Emanuel F.; Tran, Nhan L.; Bhagwat, Shripad; Tiu, Ramon; Peng, Sheng-Bin; Herring, Laura E.; Graves, Lee M.; Sers, Christine; Wood, Kris C.; Cox, Adrienne D.; Der, Channing J.
Contributor: University of Helsinki, Computational Systems Medicine
University of Helsinki, Krister Wennerberg / Principal Investigator
Date: 2020-06-16
Language: eng
Number of pages: 27
Belongs to series: Cell Reports
ISSN: 2211-1247
URI: http://hdl.handle.net/10138/317792
Abstract: We address whether combinations with a pan-RAF inhibitor (RAFi) would be effective in KRAS mutant pancreatic ductal adenocarcinoma (PDAC). Chemical library and CRISPR genetic screens identify combinations causing apoptotic anti-tumor activity. The most potent combination, concurrent inhibition of RAF (RAFi) and ERK (ERKi), is highly synergistic at low doses in cell line, organoid, and rat models of PDAC, whereas each inhibitor alone is only cytostatic. Comprehensive mechanistic signaling studies using reverse phase protein array (RPPA) pathway mapping and RNA sequencing (RNA-seq) show that RAFi/ERKi induced insensitivity to loss of negative feedback and system failures including loss of ERK signaling, FOSL1, and MYC; shutdown of the MYC transcriptome; and induction of mesenchymal-to-epithelial transition. We conclude that low-dose vertical inhibition of the RAF-MEK-ERK cascade is an effective therapeutic strategy for KRAS mutant PDAC.
Subject: CELL LUNG-CANCER
ADAPTIVE RESISTANCE
SIGNALING PATHWAYS
PANCREATIC-CANCER
ONCOGENIC KRAS
COMBINED BRAF
C-RAF
PHOSPHORYLATION
DEGRADATION
ENRICHMENT
1182 Biochemistry, cell and molecular biology
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