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초록보기

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.

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참고문헌 (25건) : 자료제공( 네이버학술정보 )

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번호 참고문헌 국회도서관 소장유무
1 State-of-the-art strategies for targeting the DNA damage response in cancer 네이버 미소장
2 Bogenberger JM, DeLeon TT, Arora M, Ahn DH, Borad MJ. Emerging role of precision medicine in biliary tract cancers. NPJ Precis Oncol. 2018;2:21. 미소장
3 Hyung J, Kim B, Yoo C, Kim KP, Jeong JH, Chang HM, et al. Clinical benefit of maintenance therapy for sdvanced biliary tract cancer patients showing no progression after first-line gemcitabine plus cisplatin. Cancer Res Treat. 2019;51:901-9. 미소장
4 Genomic spectra of biliary tract cancer. 네이버 미소장
5 Cell cycle proteins as promising targets in cancer therapy 네이버 미소장
6 Targeting WEE1 Kinase in Cancer 네이버 미소장
7 Molecular Pathways: Targeting the Protein Kinase Wee1 in Cancer. 네이버 미소장
8 Forced activation of Cdk1 via wee1 inhibition impairs homologous recombination. 네이버 미소장
9 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
10 Therapeutic implication of HER2 in advanced biliary tract cancer. 네이버 미소장
11 Nam AR, Jin MH, Park JE, Bang JH, Oh DY, Bang YJ. Therapeutic targeting of the DNA damage response using an ATR inhibitor in biliary tract cancer. Cancer Res Treat. 2019;51:1167-79. 미소장
12 Oku Y, Nishiya N, Tazawa T, Kobayashi T, Umezawa N, Sugawara Y, et al. Augmentation of the therapeutic efficacy of WEE1 kinase inhibitor AZD1775 by inhibiting the YAP-E2F1-DNA damage response pathway axis. FEBS Open Bio. 2018;8:1001-12. 미소장
13 Wright G, Golubeva V, Remsing Rix LL, Berndt N, Luo Y, Ward GA, et al. Dual targeting of WEE1 and PLK1 by AZD-1775 elicits single agent cellular anticancer activity. ACS Chem Biol. 2017;12:1883-92. 미소장
14 ATM in DNA repair in cancer 네이버 미소장
15 Targeting ATR in cancer 네이버 미소장
16 Lin X, Chen D, Zhang C, Zhang X, Li Z, Dong B, et al. Augmented antitumor activity by olaparib plus AZD1775 in gastric cancer through disrupting DNA damage repair pathways and DNA damage checkpoint. J Exp Clin Cancer Res. 2018;37:129. 미소장
17 Jin J, Fang H, Yang F, Ji W, Guan N, Sun Z, et al. Combined inhibition of ATR and WEE1 as a novel therapeutic strategy in triple-negative breast cancer. Neoplasia. 2018;20:478-88. 미소장
18 Chen D, Lin X, Gao J, Shen L, Li Z, Dong B, et al. Wee1inhibitor AZD1775 combined with cisplatin potentiates anticancer activity against gastric cancer by increasing DNA damage and cell apoptosis. Biomed Res Int. 2018;2018:5813292. 미소장
19 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
20 WEE1 inhibition targets cell cycle checkpoints for triple negative breast cancers to overcome cisplatin resistance. 네이버 미소장
21 Next‐generation sequencing survey of biliary tract cancer reveals the association between tumor somatic variants and chemotherapy resistance 네이버 미소장
22 WEE1 kinase inhibition reverses G2/M cell cycle checkpoint activation to sensitize cancer cells to immunotherapy 네이버 미소장
23 Inhibition of ATR downregulates PD-L1 and sensitizes tumor cells to T cell-mediated killing. 네이버 미소장
24 Anti-tumor activity of the ATR inhibitor AZD6738 in HER2 positive breast cancer cells. 네이버 미소장
25 Akt promotes post-irradiation survival of human tumor cells through initiation, progression, and termination of DNA-PKcs-dependent DNA double-strand break repair. 네이버 미소장

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