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Gastrointestinal cancer
Inhibition of WEE1 Potentiates Sensitivity to PARP Inhibitor in Biliary Tract Cancer
Hye-Rim Seo, Ah-Rong Nam, Ju-Hee Bang, Kyoung-Seok Oh, Jae-Min Kim, Jeesun Yoon, Tae-Yong Kim, Do-Youn Oh
Cancer Res Treat. 2022;54(2):541-553.   Published online August 6, 2021
DOI: https://doi.org/10.4143/crt.2021.473
AbstractAbstract PDFPubReaderePub
Purpose
Up to 20% of patients with biliary tract cancer (BTC) have alterations in DNA damage response (DDR) genes, including homologous recombination (HR) genes. Therefore, the DDR pathway could be a promising target for new drug development in BTC. We aim to investigate the anti-tumor effects using poly(ADP-ribose) polymerase (PARP) and WEE1 inhibitors in BTC.
Materials and Methods
We used 10 BTC cell lines to evaluate an anti-tumor effect of olaparib (a PARP inhibitor) and AZD1775 (a WEE1 inhibitor) in in vitro. Additionally, we established SNU869 xenograft model for in vivo experiments.
Results
In this study, we observed a modest anti-proliferative effect of olaparib. DNA double-strand break (DSB) and apoptosis were increased by olaparib in BTC cells. However, olaparib-induced DNA DSB was repaired through the HR pathway, and G2 arrest was induced to secure the time for repair. As AZD1775 typically regulates the G2/M checkpoint, we combined olaparib with AZD1775 to abrogate G2 arrest. We observed that AZD1775 downregulated p-CDK1, a G2/M cell cycle checkpoint protein, and induced early mitotic entry. AZD1775 also decreased CtIP and RAD51 expression and disrupted HR repair. In xenograft model, olaparib plus AZD1775 treatment reduced tumor growth more potently than did monotherapy with either drug.
Conclusion
This is the first study to suggest that olaparib combined with AZD1775 can induce synergistic anti-tumor effects against BTC. Combination therapy that blocks dual PARP and WEE1 has the potential to be further clinically developed for BTC patients.

Citations

Citations to this article as recorded by  
  • Current and Future Therapeutic Targets for Directed Molecular Therapies in Cholangiocarcinoma
    Philipp Heumann, Andreas Albert, Karsten Gülow, Denis Tümen, Martina Müller, Arne Kandulski
    Cancers.2024; 16(9): 1690.     CrossRef
  • Combined strategies with PARP inhibitors for the treatment of BRCA wide type cancer
    Yijun Xie, Di Xiao, Duo Li, Mei Peng, Wei Peng, Huaxin Duan, Xiaoping Yang
    Frontiers in Oncology.2024;[Epub]     CrossRef
  • Update on Combination Strategies of PARP Inhibitors
    Zhuoqun Lin, Lingfang Wang, Ziyu Xing, Fenfen Wang, Xiaodong Cheng
    Cancer Control.2024;[Epub]     CrossRef
  • The mechanism and clinical application of DNA damage repair inhibitors combined with immune checkpoint inhibitors in the treatment of urologic cancer
    Deqian Xie, Bowen Jiang, Shijin Wang, Qifei Wang, Guangzhen Wu
    Frontiers in Cell and Developmental Biology.2023;[Epub]     CrossRef
  • DNA Damage Response Inhibitors in Cholangiocarcinoma: Current Progress and Perspectives
    Öykü Gönül Geyik, Giulia Anichini, Engin Ulukaya, Fabio Marra, Chiara Raggi
    Cells.2022; 11(9): 1463.     CrossRef
  • Targeted Therapy of HPV Positive and Negative Tonsillar Squamous Cell Carcinoma Cell Lines Reveals Synergy between CDK4/6, PI3K and Sometimes FGFR Inhibitors, but Rarely between PARP and WEE1 Inhibitors
    Ourania N. Kostopoulou, Mark Zupancic, Mariona Pont, Emma Papin, Monika Lukoseviciute, Borja Agirre Mikelarena, Stefan Holzhauser, Tina Dalianis
    Viruses.2022; 14(7): 1372.     CrossRef
  • Targeted Therapy with PI3K, PARP, and WEE1 Inhibitors and Radiotherapy in HPV Positive and Negative Tonsillar Squamous Cell Carcinoma Cell Lines Reveals Synergy while Effects with APR-246 Are Limited
    Karin Byskata, Monika Lukoseviciute, Filippo Tuti, Mark Zupancic, Ourania N. Kostopoulou, Stefan Holzhauser, Tina Dalianis
    Cancers.2022; 15(1): 93.     CrossRef
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Inhibition of ATR Increases the Sensitivity to WEE1 Inhibitor in Biliary Tract Cancer
Ah-Rong Nam, Mei-Hua Jin, Ju-Hee Bang, Kyoung-Seok Oh, Hye-Rim Seo, Do-Youn Oh, Yung-Jue Bang
Cancer Res Treat. 2020;52(3):945-956.   Published online April 17, 2020
DOI: https://doi.org/10.4143/crt.2020.080
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Currently, the DNA damage response (DDR) pathway represents a key target for new cancer drug development. Advanced biliary tract cancer (BTC) has a poor prognosis because of the lack of efficacious treatment options. Although DNA repair pathway alterations have been reported in many patients with BTC, little is known regarding the effects of DDR-targeted agents against BTC.
Materials and Methods
In this study, nine BTC cell lines were exposed to the WEE1 inhibitor (AZD1775). In vitro, MTT assay, colony-forming assay, cell cycle analysis, phospho-histone H3 staining assay, Transwell migration assay, and western blot were performed. Then, to enhance the antitumor effect of AZD1775, the combination treatment of WEE1 inhibitor and ataxia telangiectasia mutated and Rad3 related (ATR) inhibitor (AZD6738) was conducted using MTT assay and comet assay. Finally, HuCCT-1 and SNU2670 xenograft models were established to confirm the anti-tumor effect of AZD1775 alone. Furthermore, the combination treatment was also evaluated in SNU2670 xenograft models.
Results
AZD1775 blocked the phosphorylation of CDC2 and CDC25C in all cell lines, but significantly increased apoptosis and S phase arrest in sensitive cells. However, increased p-ATR and phosphorylated ataxia telangiectasia mutated levels were observed in less sensitive cells. In addition, in vitro and in vivo data illustrated that AZD1775 combined with AZD6738 exerted more potent anti-tumor effects than either drug alone. Although WEE1 inhibition has promising anti-tumor effects in some BTC cells, the addition of ATR inhibitors could enhance its efficacy.
Conclusion
Taken together, this study supports further clinical development of DDR-targeted strategies as monotherapy or combination regimens for BTC.

Citations

Citations to this article as recorded by  
  • Current and Future Therapeutic Targets for Directed Molecular Therapies in Cholangiocarcinoma
    Philipp Heumann, Andreas Albert, Karsten Gülow, Denis Tümen, Martina Müller, Arne Kandulski
    Cancers.2024; 16(9): 1690.     CrossRef
  • Inhibition of the ATR-DNAPKcs-RB axis drives G1/S-phase transition and sensitizes triple-negative breast cancer (TNBC) to DNA holliday junctions
    Yue-miao Hu, Xue-cun Liu, Lei Hu, Zhi-wen Dong, Hong-ying Yao, Ying-jie Wang, Wen-jing Zhao, Yu-ke Xiang, Yi Liu, Hong-bo Wang, Qi-kun Yin
    Biochemical Pharmacology.2024; 225: 116310.     CrossRef
  • Combination of S-1 and the oral ATR inhibitor ceralasertib is effective against pancreatic cancer cells
    Yoshihito Morimoto, Kimihiko Takada, Ami Nakano, Osamu Takeuchi, Kazuhiro Watanabe, Masayoshi Hirohara, Yutaka Masuda
    Cancer Chemotherapy and Pharmacology.2024; 94(6): 763.     CrossRef
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    Kyoung-Seok Oh, Ah-Rong Nam, Ju-Hee Bang, Yoojin Jeong, Sea Young Choo, Hyo Jung Kim, Su In Lee, Jae-Min Kim, Jeesun Yoon, Tae-Yong Kim, Do-Youn Oh
    Cell Communication and Signaling.2024;[Epub]     CrossRef
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    Alexandre André B. A. da Costa, Dipanjan Chowdhury, Geoffrey I. Shapiro, Alan D. D’Andrea, Panagiotis A. Konstantinopoulos
    Nature Reviews Drug Discovery.2023; 22(1): 38.     CrossRef
  • Combined Inhibition of Smoothened and the DNA Damage Checkpoint WEE1 Exerts Antitumor Activity in Cholangiocarcinoma
    Giulia Anichini, Chiara Raggi, Mirella Pastore, Laura Carrassa, Luisa Maresca, Enrica Crivaro, Tiziano Lottini, Lea Duwe, Jesper B. Andersen, Lorenzo Tofani, Luca Di Tommaso, Jesus M. Banales, Annarosa Arcangeli, Fabio Marra, Barbara Stecca
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  • Inhibiting WEE1 Augments the Antitumor Efficacy of Cisplatin in Urothelial Carcinoma by Enhancing the DNA Damage Process
    Yu-Li Su, Ling-Yi Xiao, Shih-Yu Huang, Chia-Che Wu, Li-Chung Chang, Yi-Hua Chen, Hao-Lun Luo, Chun-Chieh Huang, Ting-Ting Liu, Jei-Ming Peng
    Cells.2023; 12(11): 1471.     CrossRef
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    Deqian Xie, Bowen Jiang, Shijin Wang, Qifei Wang, Guangzhen Wu
    Frontiers in Cell and Developmental Biology.2023;[Epub]     CrossRef
  • Enrichment of Wee1/CDC2 and NF-κB Signaling Pathway Constituents Mutually Contributes to CDDP Resistance in Human Osteosarcoma
    Zhengbo Hu, Lugen Li, Wenxing Lan, Xiao Wei, Xiangyuan Wen, Penghuan Wu, Xianliao Zhang, Xinhua Xi, Yufa Li, Liqi Wu, Wenhu Li, Xiaohong Liao
    Cancer Research and Treatment.2022; 54(1): 277.     CrossRef
  • ATR inhibitor AZD6738 increases the sensitivity of colorectal cancer cells to 5‑fluorouracil by inhibiting repair of DNA damage
    Takuya Suzuki, Takahisa Hirokawa, Anri Maeda, Shinnosuke Harata, Kaori Watanabe, Takeshi Yanagita, Hajime Ushigome, Nozomi Nakai, Yuzo Maeda, Kazuyoshi Shiga, Ryo Ogawa, Akira Mitsui, Masahiro Kimura, Yoichi Matsuo, Hiroki Takahashi, Shuji Takiguchi
    Oncology Reports.2022;[Epub]     CrossRef
  • Inhibition of WEE1 Potentiates Sensitivity to PARP Inhibitor in Biliary Tract Cancer
    Hye-Rim Seo, Ah-Rong Nam, Ju-Hee Bang, Kyoung-Seok Oh, Jae-Min Kim, Jeesun Yoon, Tae-Yong Kim, Do-Youn Oh
    Cancer Research and Treatment.2022; 54(2): 541.     CrossRef
  • DNA Damage Response Inhibitors in Cholangiocarcinoma: Current Progress and Perspectives
    Öykü Gönül Geyik, Giulia Anichini, Engin Ulukaya, Fabio Marra, Chiara Raggi
    Cells.2022; 11(9): 1463.     CrossRef
  • Multiple-low-dose therapy: effective killing of high-grade serous ovarian cancer cells with ATR and CHK1 inhibitors
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    NAR Cancer.2022;[Epub]     CrossRef
  • Differential Effects of Combined ATR/WEE1 Inhibition in Cancer Cells
    Gro Elise Rødland, Sissel Hauge, Grete Hasvold, Lilli T. E. Bay, Tine T. H. Raabe, Mrinal Joel, Randi G. Syljuåsen
    Cancers.2021; 13(15): 3790.     CrossRef
  • Beyond the Double-Strand Breaks: The Role of DNA Repair Proteins in Cancer Stem-Cell Regulation
    Jacqueline Nathansen, Felix Meyer, Luise Müller, Marc Schmitz, Kerstin Borgmann, Anna Dubrovska
    Cancers.2021; 13(19): 4818.     CrossRef
  • The Role of the Hedgehog Pathway in Cholangiocarcinoma
    Giulia Anichini, Laura Carrassa, Barbara Stecca, Fabio Marra, Chiara Raggi
    Cancers.2021; 13(19): 4774.     CrossRef
  • Targeting P53 as a Future Strategy to Overcome Gemcitabine Resistance in Biliary Tract Cancers
    Chiao-En Wu, Yi-Ru Pan, Chun-Nan Yeh, John Lunec
    Biomolecules.2020; 10(11): 1474.     CrossRef
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  • 266 Download
  • 18 Web of Science
  • 17 Crossref
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Therapeutic Co-targeting of WEE1 and ATM Downregulates PD-L1 Expression in Pancreatic Cancer
Mei Hua Jin, Ah-Rong Nam, Ji Eun Park, Ju-Hee Bang, Yung-Jue Bang, Do-Youn Oh
Cancer Res Treat. 2020;52(1):149-166.   Published online June 25, 2019
DOI: https://doi.org/10.4143/crt.2019.183
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Pancreatic cancer (PC) is one of the most lethal cancers worldwide, but there are currently no effective treatments. The DNA damage response (DDR) is under investigation for the development of novel anti-cancer drugs. Since DNA repair pathway alterations have been found frequently in PC, the purpose of this study was to test the DDR-targeting strategy in PC using WEE1 and ATM inhibitors.
Materials and Methods
We performed in vitro experiments using a total of ten human PC cell lines to evaluate antitumor effect of AZD1775 (WEE1 inhibitor) alone or combination with AZD0156 (ATM inhibitor). We established Capan-1–mouse model for in vivo experiments to confirm our findings.
Results
In our research, we found that WEE1 inhibitor (AZD1775) as single agent showed anti-tumor effects in PC cells, however, targeting WEE1 upregulated p-ATM level. Here, we observed that co-targeting of WEE1 and ATM acted synergistically to reduce cell proliferation and migration, and to induce DNA damage in vitro. Notably, inhibition of WEE1 or WEE1/ATM downregulated programmed cell death ligand 1 expression by blocking glycogen synthase kinase-3β serine 9 phosphorylation and decrease of CMTM6 expression. In Capan-1 mouse xenograft model, AZD1775 plus AZD0156 (ATM inhibitor) treatment reduced tumor growth and downregulated tumor expression of programmed cell death ligand 1, CMTM6, CD163, and CXCR2, all of which contribute to tumor immune evasion.
Conclusion
Dual blockade of WEE1 and ATM might be a potential therapeutic strategy for PC. Taken toget

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  • ATR inhibition amplifies antitumor effects of olaparib in biliary tract cancer
    Ah-Rong Nam, Jeesun Yoon, Mei-Hua Jin, Ju-Hee Bang, Kyoung-Seok Oh, Hye-Rim Seo, Jae-Min Kim, Tae-Yong Kim, Do-Youn Oh
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Therapeutic Targeting of the DNA Damage Response Using an ATR Inhibitor in Biliary Tract Cancer
Ah-Rong Nam, Mei Hua Jin, Ji Eun Park, Ju-Hee Bang, Do-Youn Oh, Yung-Jue Bang
Cancer Res Treat. 2019;51(3):1167-1179.   Published online December 3, 2018
DOI: https://doi.org/10.4143/crt.2018.526
AbstractAbstract PDFPubReaderePub
Purpose
The DNA damage response (DDR) is a multi-complex network of signaling pathways involved in DNA damage repair, cell cycle checkpoints, and apoptosis. In the case of biliary tract cancer (BTC), the strategy of DDR targeting has not been evaluated, even though many patients have DNA repair pathway alterations. The purpose of this study was to test the DDR-targeting strategy in BTC using an ataxia-telangiectasia and Rad3-related (ATR) inhibitor.
Materials and Methods
A total of nine human BTC cell lines were used for evaluating anti-tumor effect of AZD6738 (ATR inhibitor) alone or combination with cytotoxic chemotherapeutic agents through MTT assay, colony-forming assays, cell cycle analyses, and comet assays. We established SNU478-mouse model for in vivo experiments to confirm our findings.
Results
Among nine human BTC cell lines, SNU478 and SNU869 were the most sensitive to AZD6738, and showed low expression of both ataxia-telangiectasia mutated (ATM) and p53. AZD6738 blocked p-Chk1 and p-glycoprotein and increased γH2AX, a marker of DNA damage, in sensitive cells. AZD6738 significantly increased apoptosis, G2/M arrest and p21, and decreased CDC2. Combinations of AZD6738 and cytotoxic chemotherapeutic agents exerted synergistic effects in colony-forming assays, cell cycle analyses, and comet assays. In our mouse models, AZD6738 monotherapy decreased tumor growth and the combination with cisplatin showed more potent effects on growth inhibition, decreased Ki-67, and increased terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling than monotherapy with each drug.
Conclusion
In BTC, DDR targeting strategy using ATR inhibitor demonstrated promising antitumor activity alone or in combination with cytotoxic chemotherapeutic agents. This supports further clinical development of DDR targeting strategy in BTC.

Citations

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Interactome Analysis Reveals that Heterochromatin Protein 1γ (HP1γ) Is Associated with the DNA Damage Response Pathway
Hongtae Kim, Jae Duk Choi, Byung-Gyu Kim, Ho Chul Kang, Jong-Soo Lee
Cancer Res Treat. 2016;48(1):322-333.   Published online March 6, 2015
DOI: https://doi.org/10.4143/crt.2014.294
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Heterochromatin protein 1γ (HP1γ) interacts with chromosomes by binding to lysine 9-methylated histone H3 or DNA/RNA. HP1γ is involved in various biological processes. The purpose of this study is to gain an understanding of how HP1γ functions in these processes by identifying HP1γ-binding proteins using mass spectrometry.
Materials and Methods
We performed affinity purification of HP1γ-binding proteins using G1/S phase or prometaphase HEK293T cell lysates that transiently express mock or FLAG-HP1γ. Coomassie staining was performed for HP1γ-binding complexes, using cell lysates prepared by affinity chromatography FLAG-agarose beads, and the bands were digested and then analyzed using a mass spectrometry.
Results
We identified 99 HP1γ-binding proteins with diverse cellular functions, including spliceosome, regulation of the actin cytoskeleton, tight junction, pathogenic Escherichia coli infection, mammalian target of rapamycin signaling pathway, nucleotide excision repair, DNA replication, homologous recombination, and mismatch repair.
Conclusion
Our results suggested that HP1γ is functionally active in DNA damage response via proteinprotein interaction.

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