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학술연구/단체지원/교육 등 연구자 활동을 지속하도록 DBpia가 지원하고 있어요.
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논문 기본 정보
- 자료유형
- 학술저널
- 저자정보
- 발행연도
- 2020.1
- 수록면
- 149 - 166 (18page)
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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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참고문헌 (33)
참고문헌 신청
Bailey P / 2016 / Genomic analyses identify molecular subtypes of pancreatic cancer / Nature 531:47~52
최연악 / 2016 / Concurrent Chemoradiotherapy Versus Chemotherapy Alone for Unresectable Locally Advanced Pancreatic Cancer: A Retrospective Cohort Study / Cancer Research and Treatment 48(3):1045~1055
O’Connor MJ / 2015 / Targeting the DNA damage response in cancer / Mol Cell 60:547~560
Richer AL / 2017 / WEE1 kinase inhibitor AZD1775 has preclinical efficacy in LKB1-deficient non-small cell lung cancer / Cancer Res 77:4663~4672
Kaufman B / 2015 / Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2mutation / J Clin Oncol 33:244~250
최연악 / 2016 / Concurrent Chemoradiotherapy Versus Chemotherapy Alone for Unresectable Locally Advanced Pancreatic Cancer: A Retrospective Cohort Study / Cancer Research and Treatment 48(3):1045~1055
O’Connor MJ / 2015 / Targeting the DNA damage response in cancer / Mol Cell 60:547~560
Richer AL / 2017 / WEE1 kinase inhibitor AZD1775 has preclinical efficacy in LKB1-deficient non-small cell lung cancer / Cancer Res 77:4663~4672
Kaufman B / 2015 / Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2mutation / J Clin Oncol 33:244~250
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