CHK1 protects oncogenic KRAS-expressing cells from DNA damage and is a target for pancreatic cancer treatment

Jennifer E. Klomp; Ye S. Lee; Craig M. Goodwin; Björn Papke; Jeff A. Klomp; Andrew M. Waters; Clint A. Stalnecker; Jonathan M. DeLiberty; Kristina Drizyte-Miller; Runying Yang; J. Nathaniel Diehl; Hongwei H. Yin; Mariaelena Pierobon; Elisa Baldelli; Meagan B. Ryan; Siqi Li; Jackson Peterson; Amber R. Smith; James T. Neal; Aaron K. McCormick; Calvin J. Kuo; Christopher M. Counter; Emanuel F. Petricoin; Adrienne D. Cox; Kirsten L. Bryant; Channing J. Der

doi:10.1016/j.celrep.2021.110060

CHK1 protects oncogenic KRAS-expressing cells from DNA damage and is a target for pancreatic cancer treatment

Jennifer E. Klomp, Ye S. Lee, Craig M. Goodwin, Björn Papke, Jeff A. Klomp, Andrew M. Waters, Clint A. Stalnecker, Jonathan M. DeLiberty, Kristina Drizyte-Miller, Runying Yang, J. Nathaniel Diehl, Hongwei H. Yin, Mariaelena Pierobon, Elisa Baldelli, Meagan B. Ryan, Siqi Li, Jackson Peterson, Amber R. Smith, James T. Neal, Aaron K. McCormickCalvin J. Kuo, Christopher M. Counter, Emanuel F. Petricoin, Adrienne D. Cox, Kirsten L. Bryant, Channing J. Der^*

^*Corresponding author for this work

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

21 Scopus citations

Abstract

We apply genetic screens to delineate modulators of KRAS mutant pancreatic ductal adenocarcinoma (PDAC) sensitivity to ERK inhibitor treatment, and we identify components of the ATR-CHK1 DNA damage repair (DDR) pathway. Pharmacologic inhibition of CHK1 alone causes apoptotic growth suppression of both PDAC cell lines and organoids, which correlates with loss of MYC expression. CHK1 inhibition also activates ERK and AMPK and increases autophagy, providing a mechanistic basis for increased efficacy of concurrent CHK1 and ERK inhibition and/or autophagy inhibition with chloroquine. To assess how CHK1 inhibition-induced ERK activation promotes PDAC survival, we perform a CRISPR-Cas9 loss-of-function screen targeting direct/indirect ERK substrates and identify RIF1. A key component of non-homologous end joining repair, RIF1 suppression sensitizes PDAC cells to CHK1 inhibition-mediated apoptotic growth suppression. Furthermore, ERK inhibition alone decreases RIF1 expression and phenocopies RIF1 depletion. We conclude that concurrent DDR suppression enhances the efficacy of ERK and/or autophagy inhibitors in KRAS mutant PDAC.

Original language	English
Article number	110060
Journal	Cell Reports
Volume	37
Issue number	9
DOIs	https://doi.org/10.1016/j.celrep.2021.110060
State	Published - 30 Nov 2021
Externally published	Yes

Keywords

CHK1
DNA damage
ERK
KRAS
MYC
RIF1
pancreatic cancer

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10.1016/j.celrep.2021.110060

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Klomp, J. E., Lee, Y. S., Goodwin, C. M., Papke, B., Klomp, J. A., Waters, A. M., Stalnecker, C. A., DeLiberty, J. M., Drizyte-Miller, K., Yang, R., Diehl, J. N., Yin, H. H., Pierobon, M., Baldelli, E., Ryan, M. B., Li, S., Peterson, J., Smith, A. R., Neal, J. T., ... Der, C. J. (2021). CHK1 protects oncogenic KRAS-expressing cells from DNA damage and is a target for pancreatic cancer treatment. Cell Reports, 37(9), Article 110060. https://doi.org/10.1016/j.celrep.2021.110060

@article{90e5a9a7ca4a4c9fa126a63594dfec51,

title = "CHK1 protects oncogenic KRAS-expressing cells from DNA damage and is a target for pancreatic cancer treatment",

abstract = "We apply genetic screens to delineate modulators of KRAS mutant pancreatic ductal adenocarcinoma (PDAC) sensitivity to ERK inhibitor treatment, and we identify components of the ATR-CHK1 DNA damage repair (DDR) pathway. Pharmacologic inhibition of CHK1 alone causes apoptotic growth suppression of both PDAC cell lines and organoids, which correlates with loss of MYC expression. CHK1 inhibition also activates ERK and AMPK and increases autophagy, providing a mechanistic basis for increased efficacy of concurrent CHK1 and ERK inhibition and/or autophagy inhibition with chloroquine. To assess how CHK1 inhibition-induced ERK activation promotes PDAC survival, we perform a CRISPR-Cas9 loss-of-function screen targeting direct/indirect ERK substrates and identify RIF1. A key component of non-homologous end joining repair, RIF1 suppression sensitizes PDAC cells to CHK1 inhibition-mediated apoptotic growth suppression. Furthermore, ERK inhibition alone decreases RIF1 expression and phenocopies RIF1 depletion. We conclude that concurrent DDR suppression enhances the efficacy of ERK and/or autophagy inhibitors in KRAS mutant PDAC.",

keywords = "CHK1, DNA damage, ERK, KRAS, MYC, RIF1, pancreatic cancer",

author = "Klomp, {Jennifer E.} and Lee, {Ye S.} and Goodwin, {Craig M.} and Bj{\"o}rn Papke and Klomp, {Jeff A.} and Waters, {Andrew M.} and Stalnecker, {Clint A.} and DeLiberty, {Jonathan M.} and Kristina Drizyte-Miller and Runying Yang and Diehl, {J. Nathaniel} and Yin, {Hongwei H.} and Mariaelena Pierobon and Elisa Baldelli and Ryan, {Meagan B.} and Siqi Li and Jackson Peterson and Smith, {Amber R.} and Neal, {James T.} and McCormick, {Aaron K.} and Kuo, {Calvin J.} and Counter, {Christopher M.} and Petricoin, {Emanuel F.} and Cox, {Adrienne D.} and Bryant, {Kirsten L.} and Der, {Channing J.}",

note = "Publisher Copyright: {\textcopyright} 2021 The Author(s)",

year = "2021",

month = nov,

day = "30",

doi = "10.1016/j.celrep.2021.110060",

language = "English",

volume = "37",

journal = "Cell Reports",

issn = "2211-1247",

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Klomp, JE, Lee, YS, Goodwin, CM, Papke, B, Klomp, JA, Waters, AM, Stalnecker, CA, DeLiberty, JM, Drizyte-Miller, K, Yang, R, Diehl, JN, Yin, HH, Pierobon, M, Baldelli, E, Ryan, MB, Li, S, Peterson, J, Smith, AR, Neal, JT, McCormick, AK, Kuo, CJ, Counter, CM, Petricoin, EF, Cox, AD, Bryant, KL & Der, CJ 2021, 'CHK1 protects oncogenic KRAS-expressing cells from DNA damage and is a target for pancreatic cancer treatment', Cell Reports, vol. 37, no. 9, 110060. https://doi.org/10.1016/j.celrep.2021.110060

TY - JOUR

T1 - CHK1 protects oncogenic KRAS-expressing cells from DNA damage and is a target for pancreatic cancer treatment

AU - Klomp, Jennifer E.

AU - Lee, Ye S.

AU - Goodwin, Craig M.

AU - Papke, Björn

AU - Klomp, Jeff A.

AU - Waters, Andrew M.

AU - Stalnecker, Clint A.

AU - DeLiberty, Jonathan M.

AU - Drizyte-Miller, Kristina

AU - Yang, Runying

AU - Diehl, J. Nathaniel

AU - Yin, Hongwei H.

AU - Pierobon, Mariaelena

AU - Baldelli, Elisa

AU - Ryan, Meagan B.

AU - Li, Siqi

AU - Peterson, Jackson

AU - Smith, Amber R.

AU - Neal, James T.

AU - McCormick, Aaron K.

AU - Kuo, Calvin J.

AU - Counter, Christopher M.

AU - Petricoin, Emanuel F.

AU - Cox, Adrienne D.

AU - Bryant, Kirsten L.

AU - Der, Channing J.

PY - 2021/11/30

Y1 - 2021/11/30

N2 - We apply genetic screens to delineate modulators of KRAS mutant pancreatic ductal adenocarcinoma (PDAC) sensitivity to ERK inhibitor treatment, and we identify components of the ATR-CHK1 DNA damage repair (DDR) pathway. Pharmacologic inhibition of CHK1 alone causes apoptotic growth suppression of both PDAC cell lines and organoids, which correlates with loss of MYC expression. CHK1 inhibition also activates ERK and AMPK and increases autophagy, providing a mechanistic basis for increased efficacy of concurrent CHK1 and ERK inhibition and/or autophagy inhibition with chloroquine. To assess how CHK1 inhibition-induced ERK activation promotes PDAC survival, we perform a CRISPR-Cas9 loss-of-function screen targeting direct/indirect ERK substrates and identify RIF1. A key component of non-homologous end joining repair, RIF1 suppression sensitizes PDAC cells to CHK1 inhibition-mediated apoptotic growth suppression. Furthermore, ERK inhibition alone decreases RIF1 expression and phenocopies RIF1 depletion. We conclude that concurrent DDR suppression enhances the efficacy of ERK and/or autophagy inhibitors in KRAS mutant PDAC.

AB - We apply genetic screens to delineate modulators of KRAS mutant pancreatic ductal adenocarcinoma (PDAC) sensitivity to ERK inhibitor treatment, and we identify components of the ATR-CHK1 DNA damage repair (DDR) pathway. Pharmacologic inhibition of CHK1 alone causes apoptotic growth suppression of both PDAC cell lines and organoids, which correlates with loss of MYC expression. CHK1 inhibition also activates ERK and AMPK and increases autophagy, providing a mechanistic basis for increased efficacy of concurrent CHK1 and ERK inhibition and/or autophagy inhibition with chloroquine. To assess how CHK1 inhibition-induced ERK activation promotes PDAC survival, we perform a CRISPR-Cas9 loss-of-function screen targeting direct/indirect ERK substrates and identify RIF1. A key component of non-homologous end joining repair, RIF1 suppression sensitizes PDAC cells to CHK1 inhibition-mediated apoptotic growth suppression. Furthermore, ERK inhibition alone decreases RIF1 expression and phenocopies RIF1 depletion. We conclude that concurrent DDR suppression enhances the efficacy of ERK and/or autophagy inhibitors in KRAS mutant PDAC.

KW - CHK1

KW - DNA damage

KW - ERK

KW - KRAS

KW - MYC

KW - RIF1

KW - pancreatic cancer

UR - http://www.scopus.com/inward/record.url?scp=85119927038&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2021.110060

DO - 10.1016/j.celrep.2021.110060

M3 - Article

C2 - 34852220

AN - SCOPUS:85119927038

SN - 2211-1247

VL - 37

JO - Cell Reports

JF - Cell Reports

IS - 9

M1 - 110060

ER -

CHK1 protects oncogenic KRAS-expressing cells from DNA damage and is a target for pancreatic cancer treatment

Abstract

Keywords

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