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 3rd; 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

Cell Rep. 2021 Nov 30;37(9):110060. doi: 10.1016/j.celrep.2021.110060.

Authors

Jennifer E Klomp¹, Ye S Lee², Craig M Goodwin¹, Björn Papke¹, Jeff A Klomp¹, Andrew M Waters¹, Clint A Stalnecker¹, Jonathan M DeLiberty², Kristina Drizyte-Miller¹, Runying Yang¹, J Nathaniel Diehl³, Hongwei H Yin⁴, Mariaelena Pierobon⁵, Elisa Baldelli⁵, Meagan B Ryan², Siqi Li⁶, Jackson Peterson⁶, Amber R Smith⁷, James T Neal⁷, Aaron K McCormick⁷, Calvin J Kuo⁷, Christopher M Counter⁶, Emanuel F Petricoin 3rd⁵, Adrienne D Cox⁸, Kirsten L Bryant⁹, Channing J Der¹⁰

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].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Apoptosis
Carcinoma, Pancreatic Ductal / drug therapy*
Carcinoma, Pancreatic Ductal / genetics
Carcinoma, Pancreatic Ductal / metabolism
Carcinoma, Pancreatic Ductal / pathology
Cell Proliferation
Checkpoint Kinase 1 / antagonists & inhibitors*
Checkpoint Kinase 1 / genetics
Checkpoint Kinase 1 / metabolism
DNA Damage*
Humans
Mice
Mutation*
Pancreatic Neoplasms / drug therapy*
Pancreatic Neoplasms / genetics
Pancreatic Neoplasms / metabolism
Pancreatic Neoplasms / pathology
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins p21(ras) / genetics*
Proto-Oncogene Proteins p21(ras) / metabolism
Xenograft Model Antitumor Assays

Substances

KRAS protein, human
Protein Kinase Inhibitors
CHEK1 protein, human
Checkpoint Kinase 1
Proto-Oncogene Proteins p21(ras)

Abstract

Publication types

MeSH terms

Substances

Grants and funding