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Klomp JE, Lee YS, Goodwin CM, et al. CHK1 protects oncogenic KRAS-expressing cells from DNA damage and is a target for pancreatic cancer treatment. Cell Rep. 2021;37(9):110060doi: 10.1016/j.celrep.2021.110060.
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., McCormick, A. K., Kuo, C. J., Counter, C. M., Petricoin, E. F., Cox, A. D., Bryant, K. L., & 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), 110060. https://doi.org/10.1016/j.celrep.2021.110060
Klomp, Jennifer E, et al. "CHK1 protects oncogenic KRAS-expressing cells from DNA damage and is a target for pancreatic cancer treatment." Cell reports vol. 37,9 (2021): 110060. doi: https://doi.org/10.1016/j.celrep.2021.110060
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. CHK1 protects oncogenic KRAS-expressing cells from DNA damage and is a target for pancreatic cancer treatment. Cell Rep. 2021 Nov 30;37(9):110060. doi: 10.1016/j.celrep.2021.110060. PMID: 34852220; PMCID: PMC8665414.
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Cell Rep. 2021 Nov 30;37(9):110060. doi: 10.1016/j.celrep.2021.110060.

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

Cell reports

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

Affiliations

  1. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  2. Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  3. Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  4. Departments of Cancer and Cell Biology, Translational Genomics Research Institute, Phoenix, AZ, USA.
  5. Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA.
  6. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC.
  7. Department of Medicine, Stanford University, Stanford University School of Medicine, Stanford, CA 94305, USA.
  8. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  9. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  10. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: [email protected].

PMID: 34852220 PMCID: PMC8665414 DOI: 10.1016/j.celrep.2021.110060

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.

Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Keywords: CHK1; DNA damage; ERK; KRAS; MYC; RIF1; pancreatic cancer

Conflict of interest statement

Declaration of interests C.J.D. is a consultant/advisory board member for Anchiano Therapeutics, Deciphera Pharmaceuticals, Mirati Therapeutics, and Revolution Medicines. C.J.D. has received research

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