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

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 RA...

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Autores principales: 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 V., Tiu, Ramon V., Peng, Sheng-Bin, Herring, Laura E., Graves, Lee M., Sers, Christine, Wood, Kris C., Cox, Adrienne D., Der, Channing J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393480/
https://www.ncbi.nlm.nih.gov/pubmed/32553168
http://dx.doi.org/10.1016/j.celrep.2020.107764
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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 V.
Tiu, Ramon V.
Peng, Sheng-Bin
Herring, Laura E.
Graves, Lee M.
Sers, Christine
Wood, Kris C.
Cox, Adrienne D.
Der, Channing J.
author_facet 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 V.
Tiu, Ramon V.
Peng, Sheng-Bin
Herring, Laura E.
Graves, Lee M.
Sers, Christine
Wood, Kris C.
Cox, Adrienne D.
Der, Channing J.
author_sort Ozkan-Dagliyan, Irem
collection PubMed
description 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.
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spelling pubmed-73934802020-07-31 Low-Dose Vertical Inhibition of the RAF-MEK-ERK Cascade Causes Apoptotic Death of KRAS Mutant Cancers 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 V. Tiu, Ramon V. Peng, Sheng-Bin Herring, Laura E. Graves, Lee M. Sers, Christine Wood, Kris C. Cox, Adrienne D. Der, Channing J. Cell Rep Article 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. 2020-06-16 /pmc/articles/PMC7393480/ /pubmed/32553168 http://dx.doi.org/10.1016/j.celrep.2020.107764 Text en This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
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 V.
Tiu, Ramon V.
Peng, Sheng-Bin
Herring, Laura E.
Graves, Lee M.
Sers, Christine
Wood, Kris C.
Cox, Adrienne D.
Der, Channing J.
Low-Dose Vertical Inhibition of the RAF-MEK-ERK Cascade Causes Apoptotic Death of KRAS Mutant Cancers
title Low-Dose Vertical Inhibition of the RAF-MEK-ERK Cascade Causes Apoptotic Death of KRAS Mutant Cancers
title_full Low-Dose Vertical Inhibition of the RAF-MEK-ERK Cascade Causes Apoptotic Death of KRAS Mutant Cancers
title_fullStr Low-Dose Vertical Inhibition of the RAF-MEK-ERK Cascade Causes Apoptotic Death of KRAS Mutant Cancers
title_full_unstemmed Low-Dose Vertical Inhibition of the RAF-MEK-ERK Cascade Causes Apoptotic Death of KRAS Mutant Cancers
title_short Low-Dose Vertical Inhibition of the RAF-MEK-ERK Cascade Causes Apoptotic Death of KRAS Mutant Cancers
title_sort low-dose vertical inhibition of the raf-mek-erk cascade causes apoptotic death of kras mutant cancers
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393480/
https://www.ncbi.nlm.nih.gov/pubmed/32553168
http://dx.doi.org/10.1016/j.celrep.2020.107764
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