Cancer Research and Treatment

Original Articles

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

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.

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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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Prognostic Value of Serum Soluble Programmed Death-Ligand 1 and Dynamics During Chemotherapy in Advanced Gastric Cancer Patients: Woochan Park, Ju-Hee Bang, Ah-Rong Nam, Mei Hua Jin, Hyerim Seo, Jae-Min Kim, Kyoung Seok Oh, Tae-Yong Kim, Do-Youn Oh; Cancer Res Treat. 2021;53(1):199-206. Published online October 6, 2020; DOI: https://doi.org/10.4143/crt.2020.497

Abstract PDF Supplementary Material PubReader ePub

Purpose
The soluble form programmed death-ligand 1 (sPDL1) has immunosuppressive properties and is being studied as a candidate biomarker for immuno-oncology drug development. We measured the serum sPDL1 at pre-and post-chemotherapy and evaluated its prognostic implication and dynamics during chemotherapy in advanced gastric cancer (GC).
Materials and Methods
We prospectively enrolled 68 GC patients who were candidates for palliative standard first-line chemotherapy, and serially collected blood at baseline and after one cycle of chemotherapy, at the best response and after disease progression. sPDL1 was measured using an enzyme-linked immunosorbent assay. Response to chemotherapy, overall survival (OS), progressionfree survival (PFS) and other prognostic factors including neutrophil-lymphocyte ratio (NLR) were obtained. The cut-off value of sPDL1 levels for survival analysis was found using C-statistics.
Results
The median baseline sPDL1 was 0.8 ng/mL (range, 0.06 to 6.06 ng/mL). The median OS and PFS were 14.9 months and 8.0 months, respectively. sPDL1 and NLR showed a weak positive correlation (Spearman’s rho=0.301, p=0.013). Patients with low levels of sPDL1 at diagnosis (< 1.92 ng/mL) showed a better OS and PFS than patients with a high sPDL1. The baseline sPDL1 before treatment was higher in the progressive disease group than in the stable disease and partial response groups. Patients whose sPDL1 increased after the first cycle of chemotherapy showed worse PFS and OS. Following disease progression, sPDL1 increased compared with the baseline.
Conclusion
sPDL1 at prechemotherapy confers a prognostic value for PFS and OS in GC patients under palliative first-line chemotherapy. Dynamics of sPDL1 during chemotherapy correlates with disease progression.

Citations

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Frontiers in Oncology.2023;[Epub] CrossRef
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Journal of Clinical Medicine.2021; 10(7): 1412. 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

Abstract PDF Supplementary Material PubReader ePub

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

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Current and Future Therapeutic Targets for Directed Molecular Therapies in Cholangiocarcinoma
Philipp Heumann, Andreas Albert, Karsten Gülow, Denis Tümen, Martina Müller, Arne Kandulski
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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
Immunomodulatory effects of trastuzumab deruxtecan through the cGAS-STING pathway in gastric cancer cells
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
Targeting replication stress in cancer therapy
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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The mechanism and clinical application of DNA damage repair inhibitors combined with immune checkpoint inhibitors in the treatment of urologic cancer
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Enrichment of Wee1/CDC2 and NF-κB Signaling Pathway Constituents Mutually Contributes to CDDP Resistance in Human Osteosarcoma
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ATR inhibitor AZD6738 increases the sensitivity of colorectal cancer cells to 5‑fluorouracil by inhibiting repair of DNA damage
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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
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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

Abstract PDF Supplementary Material PubReader ePub

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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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

Abstract PDF PubReader ePub

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.

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Dynamics of Soluble Programmed Death-Ligand 1 (sPDL1) during Chemotherapy and Its Prognostic Implications in Cancer Patients: Biomarker Development in Immuno-oncology: Hyerim Ha, Ju-Hee Bang, Ah-Rong Nam, Ji-Eun Park, Mei Hua Jin, Yung-Jue Bang, Do-Youn Oh; Cancer Res Treat. 2019;51(2):832-840. Published online October 5, 2018; DOI: https://doi.org/10.4143/crt.2018.311

Abstract PDF PubReader ePub

Purpose
The soluble programmed death-ligand 1 (sPDL1) has immunosuppressive activity and is a candidate biomarker for immuno-oncology drug development. In this study, we measured sPDL1 at pre- and post-chemotherapy and at disease progression to uncover the dynamics of sPDL1 during treatment in biliary tract cancer (BTC) patients.
Materials and Methods
From 90 BTC patients (training cohort, 53; validation cohort, 37) who were candidates for palliative first-line chemotherapy, blood was collected at pre- and post-chemotherapy (at the time of best response) and at disease progression. The sPDL1 levels were measured using an enzyme-linked immunosorbent assay. Responses to chemotherapy, overall survival (OS), and other prognostic factors including the neutrophil-lymphocyte ratio (NLR) were analyzed.
Results
The OS of all patients was 11.5 months (confidence interval [CI], 9.7 to 16.2). The best response was complete response in seven (7.8%), partial response in 20 (22.2%), stable disease in 52 (57.8%), and disease progression (PD) in 11 patients (12.2%). Patients with high pre-chemotherapy sPDL1 (≥ 1.30 ng/mL) showed worse OS than patients with low prechemotherapy sPDL1 (9.1 months vs. 12.5 months, p=0.003). In multivariate analyses, high pre-chemotherapy sPDL1 (hazard ratio [HR], 1.96; 95% CI, 1.2 to 3.9; p=0.011) and high pre-chemotherapy NLR (HR, 1.82; 95% CI, 1.1 to 3.0; p=0.020) were independent poor prognostic factors for OS. At the time of PD, sPDL1 was increased significantly compared with pre-chemotherapy sPDL1 (1.59 ng/mL vs. 0.72 ng/mL, p=0.003).
Conclusion
The sPDL1 at pre-chemotherapy confers the prognostic value for OS in BTC patients under palliative chemotherapy. The dynamics of sPDL1 during chemotherapy correlate with disease burden and have prognostic value.

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Frontiers in Immunology.2020;[Epub] CrossRef

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Jab1 Silencing Inhibits Proliferation and Sensitizes to Cisplatin in Biliary Tract Cancer: Ah-Rong Nam, Ji-Won Kim, Ji Eun Park, Ju-Hee Bang, Mei Hua Jin, Do-Youn Oh, Yung-Jue Bang; Cancer Res Treat. 2019;51(3):886-900. Published online October 1, 2018; DOI: https://doi.org/10.4143/crt.2018.375

Abstract PDF Supplementary Material PubReader ePub

Purpose
Jab1 is a coactivator of c-Jun that enhances the transcriptional function of c-Jun. Jab1 is frequently overexpressed in various cancers and is associatedwith poor prognosis of cancer patients. Thus, Jab1 could be a potential therapeutic target in cancer. However, the role of Jab1 in biliary tract cancer (BTC) has not been studied.
Materials and Methods
We performed in vitro and in vivo experiments to evaluate the therapeutic potential ofJab1 inhibition in BTC.
Results
Among 8 BTC cell lines, many showed higher Jab1 expression levels. In addition, Jab1 silencing by siRNA increased p27 expression levels. SNU478 and HuCCT-1 cells exhibited profound Jab1 knockdown and increased p27 expression by Jab1-specific siRNA transfection. Jab1 silencing induced anti-proliferative and anti-migratory effects and resulted in G1 cell cycle arrest in SNU478 and HuCCT-1 cells. In addition, Jab1 silencing potentiated the anti-proliferative and anti-migratory effects of cisplatin by increasing DNA damage. Interestingly,Jab1 knockdown increased PTEN protein half-life, resulting in increased PTEN expression. In the HuCCT-1 mouse xenograft model, stable knockdown of Jab1 by shRNA also showed anti-proliferative effects in vivo, with decreased Ki-67 expression and AKT phosphorylation and increased Terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling and p27 expression.
Conclusion
Jab1 knockdown demonstrated anti-proliferative and anti-migratory effects in BTC cells by increasing DNA damage and stabilizing PTEN, resulting in G1 cell cycle arrest. In addition, Jab1 silencing potentiated the anti-proliferative effects of cisplatin. Our data suggest that Jab1 may be a potential therapeutic target in BTC that is worthy of further investigations.

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