In tumor cells regulation of DNA double strand break repair through EGF receptor involves both NHEJ and HR and is independent of p53 and K-Ras status

Myllynen, Laura; Rieckmann, Thorsten; Dahm-Daphi, Jochen; Kasten-Pisula, Ulla; Petersen, Cordula; Dikomey, Ekkehard; Kriegs, Malte

doi:10.1016/j.radonc.2011.05.046

Cited by 53 publications

(46 citation statements)

References 25 publications

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“…This is surprising, as both ATO and inhibition of EGFR and its downstream signals have been shown to result in compromised DNA repair processes (22,(34)(35)(36)(37). Interestingly, we could not detect an enhanced generation of ROS in the drug combination despite synergistic induction of DNA DSBs and subsequent phosphorylation of H2AX.…”

Section: Discussioncontrasting

confidence: 57%

“…In addition, there is increasing evidence that especially deficiency in DNA DSB repair is associated with increased sensitivity to arsenic (50). Notably, besides multiple other functions, the EGFR pathway has been recently shown to be involved in the regulation of DNA DSB repair by positive regulation of both the homologous recombination as well as the nonhomologous end-joining (22,37). Thus, activation of EGFR resulted in a decreased number of residual DNA DSBs, whereas the number of H2AX-positive DSB foci was clearly increased when EGFR was blocked by erlotinib in A549 and other lung cancer cell lines (22,34).…”

Section: Discussionmentioning

confidence: 99%

“…Notably, besides multiple other functions, the EGFR pathway has been recently shown to be involved in the regulation of DNA DSB repair by positive regulation of both the homologous recombination as well as the nonhomologous end-joining (22,37). Thus, activation of EGFR resulted in a decreased number of residual DNA DSBs, whereas the number of H2AX-positive DSB foci was clearly increased when EGFR was blocked by erlotinib in A549 and other lung cancer cell lines (22,34). Moreover, erlotinib also attenuated DNA damageinduced Rad51 foci and resulted in cytoplasmic retention of BRCA1 (37), both essential components of the DSB repair machinery.…”

Section: Discussionmentioning

confidence: 99%

“…Effects of the drug combination on DNA damage and repair Besides its oncogenic activity, EGFR has recently been shown to promote DNA DSB repair by regulation of nonhomologous end-joining (34-36) as well as homologous end-joining (22,37). To detect the amount of DNA DSBs after drug treatment, phosphorylation of H2AX histones was analyzed by immunostaining.…”

Section: Ato Synergizes With Inhibitors Of the Egfr Downstream Signalingmentioning

confidence: 99%

“…Moreover, there are several reports that the stimulation of the EGFR pathway is associated with enhanced DNA damage repair (22). Thus, based on the importance of the EGFR signaling for cell survival in malignant tissues and the discovery of several mutations leading to constitutive EGFR activation (23), this pathway was identified as an ideal target for cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

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Synergistic Anticancer Activity of Arsenic Trioxide with Erlotinib Is Based on Inhibition of EGFR-Mediated DNA Double-Strand Break Repair

Kryeziu

Jungwirth

Hoda

et al. 2013

Molecular Cancer Therapeutics

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Arsenic trioxide (ATO), one of the oldest remedies used in traditional medicine, was recently rediscovered as an anticancer drug and approved for treatment of relapsed acute promyelocytic leukemia. However, its activity against nonhematologic cancers is rather limited so far. Here, we show that inhibition of ATO-mediated EGF receptor (EGFR) activation can be used to potently sensitize diverse solid cancer types against ATO. Thus, combination of ATO and the EGFR inhibitor erlotinib exerted synergistic activity against multiple cancer cell lines. Subsequent analyses revealed that this effect was based on the blockade of ATO-induced EGFR phosphorylation leading to more pronounced G 2 -M arrest as well as enhanced and more rapid induction of apoptosis. Comparable ATO-sensitizing effects were also found with PI3K/AKT and mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitors, suggesting an essential role of the EGFRmediated downstream signaling pathway in cancer cell protection against ATO. H2AX staining and comet assay revealed that erlotinib significantly increases ATO-induced DNA double-strand breaks (DSB) well in accordance with a role of the EGFR signaling axis in DNA damage repair. Indeed, EGFR inhibition led to downregulation of several DNA DSB repair proteins such as Rad51 and Rad50 as well as reduced phosphorylation of BRCA1. Finally, the combination treatment of ATO and erlotinib was also distinctly superior to both monotreatments against the notoriously therapy-resistant human A549 lung cancer and the orthotopic p31 mesothelioma xenograft model in vivo. In conclusion, this study suggests that combination of ATO and EGFR inhibitors is a promising therapeutic strategy against various solid tumors harboring wild-type EGFR. Mol Cancer Ther; 12(6); 1073-84. Ó2013 AACR.

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Section: Discussioncontrasting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Ato Synergizes With Inhibitors Of the Egfr Downstream Signalingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Synergistic Anticancer Activity of Arsenic Trioxide with Erlotinib Is Based on Inhibition of EGFR-Mediated DNA Double-Strand Break Repair

Kryeziu

Jungwirth

Hoda

et al. 2013

Molecular Cancer Therapeutics

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Molecular targeting in combination with platinum‐based chemoradiotherapy in head and neck cancer treatment

et al. 2015

Self Cite

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Supplementing CRT with target therapeutics might only improve survival in some patients with locally advanced HNSCC. Therefore, future studies must address the underlying biological mechanisms that can have an impact on treatment response. Such knowledge is essential in order to facilitate the effective and personalized treatment of patients with locally advanced HNSCC by combining CRT and targeted therapy. © 2015 Wiley Periodicals, Inc. Head Neck 38: E2173-E2181, 2016.

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Epidermal Growth Factor and Granulocyte Colony Stimulating Factor Signaling Are Synergistic for Hematopoietic Regeneration

et al. 2017

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Hematopoietic regeneration following chemotherapy may be distinct from regeneration following radiation. While we have shown that epidermal growth factor (EGF) accelerates regeneration following radiation, its role following chemotherapy is currently unknown. We sought to identify EGF as a hematopoietic growth factor for chemotherapy-induced myelosuppression. Following 5-fluorouracil (5-FU), EGF accelerated hematopoietic stem cell regeneration and prolonged survival compared with saline-treated mice. To mitigate chemotherapy-induced injury to endothelial cells in vivo, we deleted Bax in VEcadherin cells (VEcadherinCre;Bax mice). Following 5-FU, VEcadherinCre;Bax mice displayed preserved hematopoietic stem/progenitor content compared with littermate controls. 5-FU and EGF treatment resulted in increased cellular proliferation, decreased apoptosis, and increased DNA double-strand break repair by non-homologous end-joining recombination compared with saline-treated control mice. When granulocyte colony stimulating factor (G-CSF) is given with EGF, this combination was synergistic for regeneration compared with either G-CSF or EGF alone. EGF increased G-CSF receptor (G-CSFR) expression following 5-FU. Conversely, G-CSF treatment increased both EGF receptor (EGFR) and phosphorylation of EGFR in hematopoietic stem/progenitor cells. In humans, the expression of EGFR is increased in patients with colorectal cancer treated with 5-FU compared with cancer patients not on 5-FU. Similarly, EGFR signaling is responsive to G-CSF in humans in vivo with both increased EGFR and phospho-EGFR in healthy human donors following G-CSF treatment compared with donors who did not receive G-CSF. These data identify EGF as a hematopoietic growth factor following myelosuppressive chemotherapy and that dual therapy with EGF and G-CSF may be an effective method to accelerate hematopoietic regeneration. Stem Cells 2018;36:252-264.

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In tumor cells regulation of DNA double strand break repair through EGF receptor involves both NHEJ and HR and is independent of p53 and K-Ras status

Cited by 53 publications

References 25 publications

Synergistic Anticancer Activity of Arsenic Trioxide with Erlotinib Is Based on Inhibition of EGFR-Mediated DNA Double-Strand Break Repair

Synergistic Anticancer Activity of Arsenic Trioxide with Erlotinib Is Based on Inhibition of EGFR-Mediated DNA Double-Strand Break Repair

Molecular targeting in combination with platinum‐based chemoradiotherapy in head and neck cancer treatment

Epidermal Growth Factor and Granulocyte Colony Stimulating Factor Signaling Are Synergistic for Hematopoietic Regeneration

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