A common Chk1-dependent phenotype of DNA double-strand break suppression in two distinct radioresistant cancer types
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A common Chk1-dependent phenotype of DNA double-strand break suppression in two distinct radioresistant cancer types. / Dinkelborg, Patrick H; Wang, Meng; Gheorghiu, Liliana; Gurski, Joseph M; Hong, Theodore S; Benes, Cyril H; Juric, Dejan; Jimenez, Rachel B; Borgmann, Kerstin; Willers, Henning.
In: BREAST CANCER RES TR, Vol. 174, No. 3, 04.2019, p. 605-613.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - A common Chk1-dependent phenotype of DNA double-strand break suppression in two distinct radioresistant cancer types
AU - Dinkelborg, Patrick H
AU - Wang, Meng
AU - Gheorghiu, Liliana
AU - Gurski, Joseph M
AU - Hong, Theodore S
AU - Benes, Cyril H
AU - Juric, Dejan
AU - Jimenez, Rachel B
AU - Borgmann, Kerstin
AU - Willers, Henning
PY - 2019/4
Y1 - 2019/4
N2 - PURPOSE: Triple-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.METHODS: Ten 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.RESULTS: Inhibition 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.CONCLUSIONS: Chk1 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.
AB - PURPOSE: Triple-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.METHODS: Ten 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.RESULTS: Inhibition 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.CONCLUSIONS: Chk1 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.
KW - Adenocarcinoma of Lung/genetics
KW - Biopsy
KW - Cell Line, Tumor
KW - Cell Proliferation/drug effects
KW - Cell Survival/drug effects
KW - Checkpoint Kinase 1/genetics
KW - DNA Breaks, Double-Stranded/drug effects
KW - Drug Screening Assays, Antitumor
KW - Female
KW - Gene Expression Regulation, Leukemic/drug effects
KW - Humans
KW - Lung Neoplasms/genetics
KW - MCF-7 Cells
KW - Mutation
KW - Phenylurea Compounds/pharmacology
KW - Proto-Oncogene Proteins p21(ras)/genetics
KW - Pyrazines/pharmacology
KW - Radiation Tolerance/drug effects
KW - Radiation-Sensitizing Agents/pharmacology
KW - Small Molecule Libraries/pharmacology
KW - Triple Negative Breast Neoplasms/genetics
U2 - 10.1007/s10549-018-05079-7
DO - 10.1007/s10549-018-05079-7
M3 - SCORING: Journal article
C2 - 30607635
VL - 174
SP - 605
EP - 613
JO - BREAST CANCER RES TR
JF - BREAST CANCER RES TR
SN - 0167-6806
IS - 3
ER -
