Evidence map›Paper›PMID 34852220›Full record

ArticleCell reports2021

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 and 16 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell reports, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.

0numbers the graph read from it
0cells of the map it votes in
34citing papers in PubMed
1.9field-weighted citation impact, top 13% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

34 citing papers in PubMed, 40 citations in OpenAlex.

  1. Review
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  11. Improving outcomes of patients with pancreatic cancer.Nature reviews. Clinical oncology · 2025
    Review
  12. Article
  13. Article
  14. Review
  15. The role of AMPK in pancreatic cancer: from carcinogenesis to treatment.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2025
    Review
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

26 authors at 5 institutions in 1 country.

Jennifer E KlompLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Ye S LeeDepartment of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Craig M GoodwinLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Björn PapkeLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Jeff A KlompLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Andrew M WatersLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Clint A StalneckerLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Jonathan M DeLibertyDepartment of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Kristina Drizyte-MillerLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Runying YangLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
J Nathaniel DiehlCurriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Hongwei H YinDepartments of Cancer and Cell Biology, Translational Genomics Research Institute, Phoenix, AZ, USA.
Mariaelena PierobonCenter for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA.
Elisa BaldelliCenter for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA.
Meagan B RyanDepartment of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Siqi LiDepartment of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC.
Jackson PetersonDepartment of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC.
Amber R SmithDepartment of Medicine, Stanford University, Stanford University School of Medicine, Stanford, CA 94305, USA.
James T NealDepartment of Medicine, Stanford University, Stanford University School of Medicine, Stanford, CA 94305, USA.
Aaron K McCormickDepartment of Medicine, Stanford University, Stanford University School of Medicine, Stanford, CA 94305, USA.
Calvin J KuoDepartment of Medicine, Stanford University, Stanford University School of Medicine, Stanford, CA 94305, USA.
Christopher M CounterDepartment of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC.
Emanuel F PetricoinCenter for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA.
Adrienne D CoxLineberger 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.
Kirsten L BryantLineberger 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.
Channing J DerLineberger 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: cjder@med.unc.edu.
University of North Carolina at Chapel Hill · USStanford University · USDuke Medical Center · USGeorge Mason University · USTranslational Genomics Research Institute · US

Funding

Integrated Training in Cancer Model SystemsT32CA009156 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI DER, CHANNING J. · 1985 to 2020
$19.7M
UCSF Project 1U54CA224081 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI CALVIN J KUO · 2017 to 2026
$12.9M
Washington University SPORE in Pancreatic CancerP50CA196510 · NCI · WASHINGTON UNIVERSITY · PI HAWKINS, WILLIAM G · 2016 to 2020
$10.9M
Project 4: The role of codon bias in RAS tumorigenesisP01CA203657 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI DER, CHANNING J. · 2016 to 2020
$7.9M
Targeting undruggable RAS for cancer treatmentR35CA232113 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI DER, CHANNING J. · 2018 to 2024
$6.3M
BIOLOGICAL ACTIVITY OF RAS ONCOGENESR01CA042978 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI DER, CHANNING J. · 1986 to 2017
$5.9M
CANCER CELL BIOLOGY TRAINING PROGRAMT32CA071341 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI CHANNING J. DER, Yuliya Pylayeva-Gupta · 1996 to 2026
$5.0M
Modeling KRAS-Dependent Synthetic Lethality in Human Colon OrganoidsU01CA199241 · NCI · STANFORD UNIVERSITY · PI KUO, CALVIN J, SHOKAT, KEVAN M. · 2016 to 2019
$4.3M
Mechanistic dissection and inhibitor targeting of autophagy in RAS driven cancersR37CA251877 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI BRYANT, KIRSTEN L · 2020 to 2025
$2.5M
Identification of synthetic lethal interactors in pancreatic cancerU01CA199235 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI COX, ADRIENNE D, DER, CHANNING J. · 2015 to 2019
$2.5M
Mechanisms of PAK1 activation, signaling and tumor resistanceR01CA175747 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI DER, CHANNING J., HAHN, KLAUS M. · 2014 to 2018
$1.8M
Defining the contributions of WT RAS in RAS-mutant lung cancerF32CA232529 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI STALNECKER, CLINT A · 2018 to 2021
$193k
NCI NIH HHS F30 CA243253NCI NIH HHS F32 CA221005NCI NIH HHS F32 CA232529NCI NIH HHS F32 CA239328NCI NIH HHS P01 CA203657NCI NIH HHS P50 CA196510NCI NIH HHS R01 CA042978NCI NIH HHS R01 CA175747NCI NIH HHS R35 CA232113NCI NIH HHS R37 CA251877NCI NIH HHS T32 CA009156NCI NIH HHS T32 CA071341NCI NIH HHS U01 CA199235NCI NIH HHS U01 CA199241NCI NIH HHS U54 CA224081
6 · The paper itself

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.

Indexed as

DNA DamageMutationAnimalsApoptosisCarcinoma, Pancreatic DuctalCell ProliferationCheckpoint Kinase 1HumansMicePancreatic NeoplasmsProtein Kinase InhibitorsProto-Oncogene Proteins p21(ras)Xenograft Model Antitumor AssaysCheckpoint Kinase 1CHEK1 protein, humanKRAS protein, humanProtein Kinase InhibitorsProto-Oncogene Proteins p21(ras)CHK1DNA damageERKKRASMYCpancreatic cancerRIF1

Identifiers

PMID34852220
PMCPMC8665414
OpenAlexW3216660807

What OpenQuestion holds

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LicenceCC BY
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.