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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-3! 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 together, our results support further clinical development of DDR-targeting strategies for PC.

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기사명 저자명 페이지 원문 목차
Time trends for prostate cancer incidence from 2003 to 2013 in South Korea : an age-period-cohort analysis Hyun Young Lee, Do Kyoung Kim, Seung Whan Doo, Won Jae Yang, Yun Seob Song, Bora Lee, Jae Heon Kim p. 301-308

Clinical targeted next-generation sequencing panels for detection of somatic variants in gliomas Hyemi Shin, Jason K. Sa, Joon Seol Bae, Harim Koo, Seonwhee Jin, Hee Jin Cho, Seung Won Choi, Jong Min Kyoung, Ja Yeon Kim, Yun Jee Seo ... [et al.] p. 41-50

Fibroblast growth factor receptor 1 (FGFR1) amplification detected by droplet digital polymerase chain reaction (ddPCR) is a prognostic factor in colorectal cancers Jeong Mo Bae, Xianyu Wen, Tae-Shin Kim, Yoonjin Kwak, Nam-Yun Cho, Hye Seung Lee, Gyeong Hoon Kang p. 74-84

Prevalence and predictors of sustained smoking after a cancer diagnosis in Korean Men Hye Yeon Koo, Kiheon Lee, Sang Min Park, Jooyoung Chang, Kyuwoong Kim, Seulggie Choi, Mi Hee Cho, Jihye Jun, Sung Min Kim p. 139-148

SUVmax predicts disease progression after stereotactic ablative radiotherapy in stage I non-small cell lung cancer Yoo-Kang Kwak, Hee Hyun Park, Kyu Hye Choi, Eun Young Park, Soo Yoon Sung, Sea-Won Lee, Ji Hyun Hong, Hyo Chun Lee, Ie Ryung Yoo, Yeon Sil Kim p. 85-97

Cathepsin C interacts with TNF-α/p38 MAPK signaling pathway to promote proliferation and metastasis in hepatocellular carcinoma Guo-Pei Zhang, Xiao Yue, Shao-Qiang Li p. 10-23

Magnetic resonance-based texture analysis differentiating KRAS mutation status in rectal cancer Ji Eun Oh, Min Ju Kim, Joohyung Lee, Bo Yun Hur, Bun Kim, Dae Yong Kim, Ji Yeon Baek, Hee Jin Chang, Sung Chan Park, Jae Hwan Oh, Sun Ah Cho, Dae Kyung Sohn p. 51-59

Pancreatic high-grade neuroendocrine neoplasms in the Korean population : a multicenter study Haeryoung Kim, Soyeon An, Kyoungbun Lee, Sangjeong Ahn, Do Youn Park, Jo-Heon Kim, Dong-Wook Kang, Min-Ju Kim, Mee Soo Chang, Eun Sun Jung ... [et al.] p. 263-276

Pediatric adenocarcinoma in Korea : a multicenter study Hee-Beom Yang, Jung-Man Namgoong, Ki Hoon Kim, Dae Yeon Kim, Jinyoung Park, Hyun Beak Shin, Joong Kee Youn, Sanghoon Lee, Ji Won Lee, Sung Eun Jung, Jae Hee Chung, Yun-Mee Choe, Tae Gil Heo, In Geol Ho, Hyun-Young Kim p. 117-127

Inequalities in awareness and attitude towards HPV and its vaccine between local and migrant residents who participated in cervical cancer screening in Shenzhen, China Wei Lin, Yueyun Wang, Zhihua Liu, Bin Chen, Shixin Yuan, Bo Wu, Lin Gong p. 207-217

Characterization of oncolytic vaccinia virus harboring the human IFNB1 and CES2 transgenes Euna Cho, S M Bakhtiar Ul Islam, Fen Jiang, Ju-Eun Park, Bora Lee, Nam Deuk Kim, Tae-Ho Hwang p. 309-319

Clinical outcomes of postoperative radiotherapy following radical prostatectomy in patients with localized prostate cancer : a multicenter retrospective study (KROG 18-01) of a Korean population Sung Uk Lee, Kwan Ho Cho, Won Park, Won Kyung Cho, Jae-Sung Kim, Chan Woo Wee, Young Seok Kim, Jin Ho Kim, Taek-Keun Nam, Jaeho Cho, Song Mi Jeong, Youngkyong Kim, Su Jung Shim, Youngmin Choi, Jun-Sang Kim p. 167-180

Diabetes mellitus is associated with inferior prognosis in patients with chronic lymphocytic leukemia : a propensity score-matched analysis Rui Gao, Tian-Shuo Man, Jin-Hua Liang, Li Wang, Hua-Yuan Zhu, Wei Wu, Lei Fan, Jian-Yong Li, Tao Yang, Wei Xu p. 189-206

Anterior gradient 3 promotes breast cancer development and chemotherapy response Qiao Xu, Ying Shao, Jinman Zhang, Huikun Zhang, Yawen Zhao, Xiaoli Liu, Zhifang Guo, Wei Chong, Feng Gu, Yongjie Ma p. 218-245

High-throughput multiplex immunohistochemical imaging of the tumor and its microenvironment Jiwon Koh, Yoonjin Kwak, Jin Kim, Woo Ho Kim p. 98-108

The effect of disability on the diagnosis and treatment of multiple myeloma in Korea: a national cohort study Jihyun Kwon, So Young Kim, Kyoung Eun Yeob, Hye Sook Han, Ki Hyeong Lee, Dong Wook Shin, Yeon-Yong Kim, Jong Heon Park, Jong Hyock Park p. 1-9

Comparison of the efficacy of two microsphere embolic agents for transcatheter arterial chemoembolization in hepatocellular carcinoma patients Shao-Hua Lee, Chia-Ying Lin, Ya-Chun Hsu, Yi-Sheng Liu, Ming-Tsung Chuang, Ming-Ching Ou p. 24-30

Intensity-modulated radiotherapy versus three-dimensional conformal radiotherapy in definitive chemoradiotherapy for cervical esophageal squamous cell carcinoma : comparison of survival outcomes and toxicities Nai-Bin Chen, Bo Qiu, Jun Zhang, Meng-Yun Qiang, Yu-Jia Zhu, Bin Wang, Jin-Yu Guo, Ling-Zhi Cai, Shao-Min Huang, Meng-Zhong Liu, Qun Li, Yong-Hong Hu, Qi-Wen Li, Hui Liu p. 31-40

Immunogenicity and optimal timing of 13-valent pneumococcal conjugate vaccination during adjuvant chemotherapy in gastric and colorectal cancer : a randomized controlled trial Wonyoung Choi, Jong Gwang Kim, Seung-Hoon Beom, Jun-Eul Hwang, Hyun-Jung Shim, Sang-Hee Cho, Min-Ho Shin, Sin-Ho Jung, Ik-Joo Chung, Joon Young Song, Woo Kyun Bae p. 246-253

Clinical outcomes of second-line chemotherapy after progression on Nab-paclitaxel plus gemcitabine in patients with metastatic pancreatic adenocarcinoma Kyoungmin Lee, Kyunghye Bang, Changhoon Yoo, Inhwan Hwang, Jae Ho Jeong, Heung-Moon Chang, Dongwook Oh, Tae Jun Song, Do Hyun Park, Sang Soo Lee, Sung Koo Lee, Myung-Hwan Kim, Jin-hong Park, Kyu-pyo Kim, Baek-Yeol Ryoo p. 254-262

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 p. 149-166

Disparities in the participation rate of colorectal cancer screening by fecal occult blood test among people with disabilities : a national database study in South Korea Dong Wook Shin, Dongkyung Chang, Jin Hyung Jung, Kyungdo Han, So Young Kim, Kui Son Choi, Won Chul Lee, Jong Heon Park, Jong Hyock Park p. 60-73

Osimertinib in patients with T790M-positive advanced non-small cell lung cancer : Korean subgroup analysis from phase Ⅱ studies Myung-Ju Ahn, Ji-Youn Han, Dong-Wan Kim, Byoung Chul Cho, Jin-Hyoung Kang, Sang-We Kim, James Chih-Hsin Yang, Tetsuya Mitsudomi, Jong Seok Lee p. 284-291

Clinical characteristics and outcomes of non-small cell lung cancer patients with HER2 alterations in Korea Kangkook Lee, Hyun Ae Jung, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn p. 292-300

Prognostic model for survival and recurrence in patients with early-stage cervical cancer : a Korean gynecologic oncology group study (KGOG 1028) E Sun Paik, Myong Cheol Lim, Moon-Hong Kim, Yun Hwan Kim, Eun Seop Song, Seok Ju Seong, Dong Hoon Suh, Jong-Min Lee, Chulmin Lee, Chel Hun Choi p. 320-333

Clinical characteristics of clear cell ovarian cancer : a retrospective multicenter experience of 308 patients in South Korea Hee Yeon Lee, Ji Hyung Hong, Jae Ho Byun, Hee-Jun Kim, Sun Kyung Baek, Jin Young Kim, Ki Hyang Kim, Jina Yun, Jung A Kim, Kwonoh Park ... [et al.] p. 277-283

Secondary squamous cell carcinoma of the oral cavity after nasopharyngeal carcinoma Liyuan Dai, Qigen Fang, Peng Li, Junfu Wu, Xu Zhang p. 109-116

Factors influencing imatinib-induced hepatotoxicity Ji Min Han, Jeong Yee, Yoon Sook Cho, Hye Sun Gwak p. 181-188

Identification of significant prognostic tissue markers associated with survival in upper urinary tract urothelial carcinoma patients treated with radical nephroureterectomy : a retrospective immunohistochemical analysis using tissue microarray Sung Han Kim, Weon Seo Park, Boram Park, Jinsoo Chung, Jae Young Joung, Kang Hyun Lee, Ho Kyung Seo p. 128-138

참고문헌 (33건) : 자료제공( 네이버학술정보 )

참고문헌 목록에 대한 테이블로 번호, 참고문헌, 국회도서관 소장유무로 구성되어 있습니다.
번호 참고문헌 국회도서관 소장유무
1 Genomic analyses identify molecular subtypes of pancreatic cancer. 네이버 미소장
2 Choi Y, Oh DY, Kim K, Chie EK, Kim TY, Lee KH, et al. Concurrent chemoradiotherapy versus chemotherapy alone for unresectable locally advanced pancreatic cancer: a retrospective cohort study. Cancer Res Treat. 2016;48:1045-55. 미소장
3 Targeting the DNA Damage Response in Cancer 네이버 미소장
4 Richer AL, Cala JM, O’Brien K, Carson VM, Inge LJ, Whitsett TG. WEE1 kinase inhibitor AZD1775 has preclinical efficacy in LKB1-deficient non-small cell lung cancer. Cancer Res. 2017;77:4663-72. 미소장
5 Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. 네이버 미소장
6 ATM loss leads to synthetic lethality in BRCA1 BRCT mutant mice associated with exacerbated defects in homology-directed repair. 네이버 미소장
7 ATR pathway inhibition is synthetically lethal in cancer cells with ERCC1 deficiency. 네이버 미소장
8 Targeting WEE1 Kinase in Cancer 네이버 미소장
9 Understanding the tumor immune microenvironment (TIME) for effective therapy 네이버 미소장
10 CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma 네이버 미소장
11 Oncology Meets Immunology: The Cancer-Immunity Cycle 네이버 미소장
12 CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity 네이버 미소장
13 DNA damage and innate immunity: links and trade-offs 네이버 미소장
14 Beyond DNA repair, the immunological role of PARP-1 and its siblings. 네이버 미소장
15 Sato H, Niimi A, Yasuhara T, Permata TB, Hagiwara Y, Isono M, et al. DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells. Nat Commun. 2017;8:1751. 미소장
16 PARP Inhibitor Upregulates PD-L1 Expression and Enhances Cancer-Associated Immunosuppression. 네이버 미소장
17 Gelatinase B/MMP-9 in Tumour Pathogenesis and Progression 네이버 미소장
18 Gialeli C, Theocharis AD, Karamanos NK. Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS J. 2011;278:16-27. 미소장
19 Interleukin-8 and interleukin-17 for cancer. 네이버 미소장
20 CCL5/CCR5 axis promotes the motility of human oral cancer cells. 네이버 미소장
21 CCL2 increases MMP-9 expression and cell motility in human chondrosarcoma cells via the Ras/Raf/MEK/ERK/NF-κB signaling pathway 네이버 미소장
22 Immune Checkpoint Blockade: A Common Denominator Approach to Cancer Therapy 네이버 미소장
23 Li CW, Lim SO, Xia W, Lee HH, Chan LC, Kuo CW, et al. Glycosylation and stabilization of programmed death ligand-1suppresses T-cell activity. Nat Commun. 2016;7:12632. 미소장
24 State-of-the-art strategies for targeting the DNA damage response in cancer 네이버 미소장
25 Chen D, Lin X, Gao J, Shen L, Li Z, Dong B, et al. Wee1 inhibitor AZD1775 combined with cisplatin potentiates anticancer activity against gastric cancer by increasing DNA damage and cell apoptosis. Biomed Res Int. 2018;2018:5813292. 미소장
26 Chen WT, Ebelt ND, Stracker TH, Xhemalce B, Van Den Berg CL, Miller KM. ATM regulation of IL-8 links oxidative stress to cancer cell migration and invasion. Elife. 2015;4:e07270. 미소장
27 Monocyte subpopulations in angiogenesis. 네이버 미소장
28 Kolli-Bouhafs K, Sick E, Noulet F, Gies JP, De Mey J, Ronde P. FAK competes for Src to promote migration against invasion in melanoma cells. Cell Death Dis. 2014;5:e1379. 미소장
29 CREB promotes laryngeal cancer cell migration via MYCT1/NAT10 axis. 네이버 미소장
30 Interferon Receptor Signaling Pathways Regulating PD-L1 and PD-L2 Expression 네이버 미소장
31 PD-L1 expression is regulated by both DNA methylation and NF-kB during EMT signaling in non-small cell lung carcinoma 네이버 미소장
32 HIP1R targets PD-L1 to lysosomal degradation to alter T cell–mediated cytotoxicity 네이버 미소장
33 TAMeless traitors: macrophages in cancer progression and metastasis 네이버 미소장

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