Evidence map›Paper›PMID 30607635›Full record

ArticleBreast cancer research and treatment2019

A common Chk1-dependent phenotype of DNA double-strand break suppression in two distinct radioresistant cancer types.

Patrick H Dinkelborg, Meng Wang, Liliana Gheorghiu, Joseph M Gurski, Theodore S Hong, Cyril H Benes, Dejan Juric, Rachel B Jimenez, Kerstin Borgmann, Henning Willers

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Breast cancer research and treatment, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.

0numbers the graph read from it
0cells of the map it votes in
9citing papers in PubMed
1.2field-weighted citation impact, top 22% 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

9 citing papers in PubMed, 17 citations in OpenAlex.

  1. KRASCellular & molecular biology letters · 2026
    Article
  2. Article
  3. Review
  4. Review
  5. Article
  6. Review
  7. Article
  8. Article
  9. Article
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

10 authors at 2 institutions in 2 countries.

Patrick H DinkelborgDepartment of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.
Meng WangDepartment of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.
Liliana GheorghiuDepartment of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.
Joseph M GurskiDepartment of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA.
Theodore S HongDepartment of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.
Cyril H BenesCenter for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
Dejan JuricDepartment of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA.
Rachel B JimenezDepartment of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.
Kerstin BorgmannLaboratory of Radiobiology and Experimental Radiooncology, Clinic of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Henning WillersDepartment of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA. hwillers@partners.org.ORCID http://orcid.org/0000-0002-3938-5732
Harvard University · USUniversität Hamburg · DE

Funding

High-Throughput Screening and Validation of Molecular Targeted ChemoradiosensitizersU01CA220714 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI HATA, AARON N, WILLERS, HENNING · 2018 to 2022
$3.1M
American Cancer Society 123420RSG-12-224-01-DMCNCI NIH HHS U01 CA220714NCI NIH HHS U01CA220714Wellcome Trust 102696WERNER-OTTO-STIFTUNG HAMBURG N/A
6 · The paper itself

Abstract

purposeTriple-negative breast cancers (TNBC) are often resistant to treatment with ionizing radiation (IR). We sought to investigate whether pharmacologic inhibition of Chk1 kinase, which is commonly overexpressed in TNBC, preferentially sensitizes TNBC cells to IR.

methodsTen breast cancer cell lines were screened with small molecule inhibitors against Chk1 and other kinases. Chk1 inhibition was also tested in isogenic KRAS mutant or wild-type cancer cells. Cellular radiosensitization was measured by short-term and clonogenic survival assays and by staining for the DNA double-strand break (DSB) marker γ-H2AX. Radiosensitization was also assessed in breast cancer biopsies using an ex vivo assay. Aurora B kinase-dependent mitosis-like chromatin condensation, a marker of radioresistance, was detected using a specific antibody against co-localized phosphorylation of serine 10 and trimethylation of lysine 9 on histone 3 (H3K9me3/S10p). Expression of CHEK1 and associated genes was evaluated in TNBC and lung adenocarcinoma.

resultsInhibition of Chk1 kinase preferentially radiosensitized TNBC cells in vitro and in patient biopsies. Interestingly, TNBC cells displayed lower numbers of IR-induced DSBs than non-TNBC cells, correlating with their observed radioresistance. We found that Chk1 suppressed IR-induced DSBs in these cells, which was dependent on H3K9me3/S10p-a chromatin mark previously found to indicate radioresistance in KRAS mutant cancers. Accordingly, the effects of Chk1 inhibition in TNBC were reproduced in KRAS mutant but not wild-type cells. We also observed co-expression of genes in this Chk1 chromatin pathway in TNBC and KRAS mutant lung cancers.

conclusionsChk1 promotes an unexpected, common phenotype of chromatin-dependent DSB suppression in radioresistant TNBC and KRAS mutant cancer cells, providing a direction for future investigations into overcoming the treatment resistance of TNBC.

Indexed as

Adenocarcinoma of LungBiopsyCell Line, TumorCell ProliferationCell SurvivalCheckpoint Kinase 1DNA Breaks, Double-StrandedDrug Screening Assays, AntitumorFemaleGene Expression Regulation, LeukemicHumansLung NeoplasmsMCF-7 CellsMutationPhenylurea CompoundsProto-Oncogene Proteins p21(ras)Checkpoint Kinase 1CHEK1 protein, humanKRAS protein, humanLY2603618Phenylurea CompoundsProto-Oncogene Proteins p21(ras)PyrazinesRadiation-Sensitizing AgentsSmall Molecule LibrariesChk1DNA double-strand breaksRadioresistanceRadiosensitizationTriple-negative breast cancer

Identifiers

PMID30607635
PMCPMC6440812
OpenAlexW2908330127

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

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.