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

Irem Ozkan-Dagliyan; J. Nathaniel Diehl; Samuel D. George; Antje Schaefer; Bjoern Papke; Kathleen Klotz-Noack; Andrew M. Waters; Craig M. Goodwin; Prson Gautam; Mariaelena Pierobon; Sen Peng; Thomas S.K. Gilbert; Kevin H. Lin; Onur Dagliyan; Krister Wennerberg; Emanuel F. Petricoin; Nhan L. Tran; Shripad V. Bhagwat; Ramon V. Tiu; Sheng Bin Peng; Laura E. Herring; Lee M. Graves; Christine Sers; Kris C. Wood; Adrienne D. Cox; Channing J. Der

doi:10.1016/j.celrep.2020.107764

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

Irem Ozkan-Dagliyan, J. Nathaniel Diehl, Samuel D. George, Antje Schaefer, Bjoern Papke, Kathleen Klotz-Noack, Andrew M. Waters, Craig M. Goodwin, Prson Gautam, Mariaelena Pierobon, Sen Peng, Thomas S.K. Gilbert, Kevin H. Lin, Onur Dagliyan, Krister Wennerberg, Emanuel F. Petricoin, Nhan L. Tran, Shripad V. Bhagwat, Ramon V. Tiu, Sheng Bin PengLaura E. Herring, Lee M. Graves, Christine Sers, Kris C. Wood, Adrienne D. Cox, Channing J. Der^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

67 Scopus citations

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.

Original language	English
Article number	107764
Journal	Cell Reports
Volume	31
Issue number	11
DOIs	https://doi.org/10.1016/j.celrep.2020.107764
State	Published - 16 Jun 2020
Externally published	Yes

Keywords

ERK
FOSL1
KRAS
MYC
RAF
mesenchymal-to-epithelial transition
pancreatic cancer

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10.1016/j.celrep.2020.107764

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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. V., Tiu, R. V., ... Der, C. J. (2020). Low-Dose Vertical Inhibition of the RAF-MEK-ERK Cascade Causes Apoptotic Death of KRAS Mutant Cancers. Cell Reports, 31(11), Article 107764. https://doi.org/10.1016/j.celrep.2020.107764

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

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.",

keywords = "ERK, FOSL1, KRAS, MYC, RAF, mesenchymal-to-epithelial transition, pancreatic cancer",

author = "Irem Ozkan-Dagliyan and Diehl, {J. Nathaniel} and George, {Samuel D.} and Antje Schaefer and Bjoern Papke and Kathleen Klotz-Noack and Waters, {Andrew M.} and Goodwin, {Craig M.} and Prson Gautam and Mariaelena Pierobon and Sen Peng and Gilbert, {Thomas S.K.} and Lin, {Kevin H.} and Onur Dagliyan and Krister Wennerberg and Petricoin, {Emanuel F.} and Tran, {Nhan L.} and Bhagwat, {Shripad V.} and Tiu, {Ramon V.} and Peng, {Sheng Bin} and Herring, {Laura E.} and Graves, {Lee M.} and Christine Sers and Wood, {Kris C.} and Cox, {Adrienne D.} and Der, {Channing J.}",

note = "Publisher Copyright: {\textcopyright} 2020 The Author(s)",

year = "2020",

month = jun,

day = "16",

doi = "10.1016/j.celrep.2020.107764",

language = "English",

volume = "31",

journal = "Cell Reports",

issn = "2211-1247",

number = "11",

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Ozkan-Dagliyan, I, Diehl, JN, George, SD, Schaefer, A, Papke, B, Klotz-Noack, K, Waters, AM, Goodwin, CM, Gautam, P, Pierobon, M, Peng, S, Gilbert, TSK, Lin, KH, Dagliyan, O, Wennerberg, K, Petricoin, EF, Tran, NL, Bhagwat, SV, Tiu, RV, Peng, SB, Herring, LE, Graves, LM, Sers, C, Wood, KC, Cox, AD & Der, CJ 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

TY - JOUR

T1 - Low-Dose Vertical Inhibition of the RAF-MEK-ERK Cascade Causes Apoptotic Death of KRAS Mutant Cancers

AU - Ozkan-Dagliyan, Irem

AU - Diehl, J. Nathaniel

AU - George, Samuel D.

AU - Schaefer, Antje

AU - Papke, Bjoern

AU - Klotz-Noack, Kathleen

AU - Waters, Andrew M.

AU - Goodwin, Craig M.

AU - Gautam, Prson

AU - Pierobon, Mariaelena

AU - Peng, Sen

AU - Gilbert, Thomas S.K.

AU - Lin, Kevin H.

AU - Dagliyan, Onur

AU - Wennerberg, Krister

AU - Petricoin, Emanuel F.

AU - Tran, Nhan L.

AU - Bhagwat, Shripad V.

AU - Tiu, Ramon V.

AU - Peng, Sheng Bin

AU - Herring, Laura E.

AU - Graves, Lee M.

AU - Sers, Christine

AU - Wood, Kris C.

AU - Cox, Adrienne D.

AU - Der, Channing J.

PY - 2020/6/16

Y1 - 2020/6/16

N2 - 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.

AB - 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.

KW - ERK

KW - FOSL1

KW - KRAS

KW - MYC

KW - RAF

KW - mesenchymal-to-epithelial transition

KW - pancreatic cancer

UR - http://www.scopus.com/inward/record.url?scp=85086391632&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2020.107764

DO - 10.1016/j.celrep.2020.107764

M3 - Article

C2 - 32553168

AN - SCOPUS:85086391632

SN - 2211-1247

VL - 31

JO - Cell Reports

JF - Cell Reports

IS - 11

M1 - 107764

ER -

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

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Keywords

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