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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
  • 7,127 View
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  • 10 Web of Science
  • 7 Crossref
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General
Pan-cancer Analysis of Tumor Mutational Burden and Homologous Recombination DNA Damage Repair Using Targeted Next-Generation Sequencing
Hai-Yun Wang, Ling Deng, Ying-Qing Li, Xiao Zhang, Ya-Kang Long, Xu Zhang, Yan-Fen Feng, Yuan He, Tao Tang, Xin-Hua Yang, Fang Wang
Cancer Res Treat. 2021;53(4):973-982.   Published online February 18, 2021
DOI: https://doi.org/10.4143/crt.2020.798
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Current variability in methods for tumor mutational burden (TMB) estimation and reporting demonstrates the urgent need for a homogeneous TMB assessment approach. Here, we compared TMB distributions in different cancer types using two customized targeted panels commonly used in clinical practice.
Materials and Methods
TMB spectra of 295- and 1021-gene panels in multiple cancer types were compared using targeted next-generation sequencing (NGS). The TMB distributions across a diverse cohort of 2,332 cancer cases were then investigated for their associations with clinical features. Treatment response data were collected for 222 patients who received immune-checkpoint inhibitors (ICIs) and their homologous recombination DNA damage repair (HR-DDR) and programmed death-ligand 1 (PD-L1) expression were additionally assessed and compared with the TMB and response rate.
Results
The median TMB between gene panels was similar despite a wide range in TMB values. The highest TMB was 8 and 10 in patients with squamous cell carcinoma and esophageal carcinoma according to the classification of histopathology and cancer types, respectively. Twenty-three out of 103 patients (22.3%) were HR-DDR‒positive and could benefit from ICI therapy; out of those 23 patients, seven patients had high TMB (p=0.004). Additionally, PD-L1 expression was not associated with TMB or treatment response among patients receiving ICIs.
Conclusion
Targeted NGS assays demonstrated the ability to evaluate TMB in pan-cancer samples as a tool to predict response to ICIs. In addition, TMB integrated with HR-DDR‒positive status could be a significant biomarker for predicting ICI response in patients.

Citations

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  • Comprehensive molecular findings in primary malignant melanoma of the esophagus: A multicenter study
    Ling Deng, Hai‐Yun Wang, Chun‐Fang Hu, Xiao‐Yun Liu, Kuntai Jiang, Juan‐Juan Yong, Xiao‐Yan Wu, Kai‐Hua Guo, Fang Wang
    Pigment Cell & Melanoma Research.2024; 37(3): 363.     CrossRef
  • Genomic Features of Homologous Recombination Deficiency in Breast Cancer: Impact on Testing and Immunotherapy
    Umer Ali, Sunitha Vungarala, Venkataswarup Tiriveedhi
    Genes.2024; 15(2): 162.     CrossRef
  • Biomarkers to predict efficacy of immune checkpoint inhibitors in colorectal cancer patients: a systematic review and meta-analysis
    Hang Yu, Qingquan Liu, Keting Wu, Shuang Tang
    Clinical and Experimental Medicine.2024;[Epub]     CrossRef
  • Clinical significance of genetic profiling based on different anatomic sites in patients with mucosal melanoma who received or did not receive immune checkpoint inhibitors
    Hai-Yun Wang, Ye Liu, Ling Deng, Kuntai Jiang, Xin-Hua Yang, Xiao-Yan Wu, Kai-Hua Guo, Fang Wang
    Cancer Cell International.2023;[Epub]     CrossRef
  • Homologous recombination repair gene mutations as a predictive biomarker for immunotherapy in patients with advanced melanoma
    Zhixuan You, Meng Lv, Xuanyu He, Yingqin Pan, Junfeng Ge, Xue Hu, Yating Zheng, Mengli Huang, Chengzhi Zhou, Changxuan You
    Frontiers in Immunology.2022;[Epub]     CrossRef
  • The role of DNA damage repair (DDR) system in response to immune checkpoint inhibitor (ICI) therapy
    Congqi Shi, Kaiyu Qin, Anqi Lin, Aimin Jiang, Quan Cheng, Zaoqu Liu, Jian Zhang, Peng Luo
    Journal of Experimental & Clinical Cancer Research.2022;[Epub]     CrossRef
  • Maximizing Small Biopsy Patient Samples: Unified RNA-Seq Platform Assessment of over 120,000 Patient Biopsies
    P. Sean Walsh, Yangyang Hao, Jie Ding, Jianghan Qu, Jonathan Wilde, Ruochen Jiang, Richard T. Kloos, Jing Huang, Giulia C. Kennedy
    Journal of Personalized Medicine.2022; 13(1): 24.     CrossRef
  • 7,688 View
  • 224 Download
  • 7 Web of Science
  • 7 Crossref
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Clinical Impact of Somatic Variants in Homologous Recombination Repair-Related Genes in Ovarian High-Grade Serous Carcinoma
Min Chul Choi, Sohyun Hwang, Sewha Kim, Sang Geun Jung, Hyun Park, Won Duk Joo, Seung Hun Song, Chan Lee, Tae-Heon Kim, Haeyoun Kang, Hee Jung An
Cancer Res Treat. 2020;52(2):634-644.   Published online January 6, 2020
DOI: https://doi.org/10.4143/crt.2019.207
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
In this study, we investigated the frequencies of mutations in DNA damage repair genes including BRCA1, BRCA2, homologous recombination genes and TP53 gene in ovarian high-grade serous carcinoma, alongside those of germline and somatic BRCA mutations, with the aim of improving the identification of patients suitable for treatment with poly(ADP-ribose) polymerase inhibitors.
Materials and Methods
Tissue samples from 77 Korean patients with ovarian high-grade serous carcinoma were subjected to next-generation sequencing. Pathogenic alterations of 38 DNA damage repair genes and TP53 gene and their relationships with patient survival were examined. Additionally, we analyzed BRCA germline variants in blood samples from 47 of the patients for comparison.
Results
BRCA1, BRCA2, and TP53 mutations were detected in 28.6%, 5.2%, and 80.5% of the 77 patients, respectively. Alterations in RAD50, ATR, MSH6, MSH2, and FANCA were also identified. At least one mutation in a DNA damage repair gene was detected in 40.3% of patients (31/77). Germline and somatic BRCA mutations were found in 20 of 47 patients (42.6%), and four patients had only somatic mutations without germline mutations (8.5%, 4/47). Patients with DNA damage repair gene alterations with or without TP53mutation, exhibited better disease-free survival than those with TP53 mutation alone.
Conclusion
DNA damage repair genes were mutated in 40.3% of patients with high-grade serous carcinoma, with somatic BRCA mutations in the absence of germline mutation in 8.5%. Somatic variant examination, along with germline testing of DNA damage repair genes, has potential to detect additional candidates for PARP inhibitor treatment.

Citations

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  • Genomic instability in ovarian cancer: Through the lens of single nucleotide polymorphisms
    Harshavardhani Canchi Sistla, Srikanth Talluri, Taruna Rajagopal, Sivaramakrishnan Venkatabalasubramanian, Nageswara Rao Dunna
    Clinica Chimica Acta.2025; 565: 119992.     CrossRef
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    Caroline Stahnke Richau, Nicole de Miranda Scherer, Bruna Palma Matta, Elvismary Molina de Armas, Fábio Carvalho de Barros Moreira, Anke Bergmann, Claudia Bessa Pereira Chaves, Mariana Boroni, Anna Claudia Evangelista dos Santos, Miguel Angelo Martins Mor
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    Liujia Qian, Jianqing Zhu, Zhangzhi Xue, Yan Zhou, Nan Xiang, Hong Xu, Rui Sun, Wangang Gong, Xue Cai, Lu Sun, Weigang Ge, Yufeng Liu, Ying Su, Wangmin Lin, Yuecheng Zhan, Junjian Wang, Shuang Song, Xiao Yi, Maowei Ni, Yi Zhu, Yuejin Hua, Zhiguo Zheng, Ti
    Nature Communications.2024;[Epub]     CrossRef
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    International Journal of Molecular Sciences.2020; 21(24): 9715.     CrossRef
  • 10,396 View
  • 293 Download
  • 15 Web of Science
  • 15 Crossref
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