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Inhibition of WEE1 Potentiates Sensitivity to PARP Inhibitor in Biliary Tract Cancer
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 usin...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Korean Cancer Association
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9016294/ https://www.ncbi.nlm.nih.gov/pubmed/34352995 http://dx.doi.org/10.4143/crt.2021.473 |
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author | Seo, Hye-Rim Nam, Ah-Rong Bang, Ju-Hee Oh, Kyoung-Seok Kim, Jae-Min Yoon, Jeesun Kim, Tae-Yong Oh, Do-Youn |
author_facet | Seo, Hye-Rim Nam, Ah-Rong Bang, Ju-Hee Oh, Kyoung-Seok Kim, Jae-Min Yoon, Jeesun Kim, Tae-Yong Oh, Do-Youn |
author_sort | Seo, Hye-Rim |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9016294 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Korean Cancer Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-90162942022-04-27 Inhibition of WEE1 Potentiates Sensitivity to PARP Inhibitor in Biliary Tract Cancer Seo, Hye-Rim Nam, Ah-Rong Bang, Ju-Hee Oh, Kyoung-Seok Kim, Jae-Min Yoon, Jeesun Kim, Tae-Yong Oh, Do-Youn Cancer Res Treat Original Article 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. Korean Cancer Association 2022-04 2021-08-06 /pmc/articles/PMC9016294/ /pubmed/34352995 http://dx.doi.org/10.4143/crt.2021.473 Text en Copyright © 2022 by the Korean Cancer Association https://creativecommons.org/licenses/by-nc/4.0/This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Article Seo, Hye-Rim Nam, Ah-Rong Bang, Ju-Hee Oh, Kyoung-Seok Kim, Jae-Min Yoon, Jeesun Kim, Tae-Yong Oh, Do-Youn Inhibition of WEE1 Potentiates Sensitivity to PARP Inhibitor in Biliary Tract Cancer |
title | Inhibition of WEE1 Potentiates Sensitivity to PARP Inhibitor in Biliary Tract Cancer |
title_full | Inhibition of WEE1 Potentiates Sensitivity to PARP Inhibitor in Biliary Tract Cancer |
title_fullStr | Inhibition of WEE1 Potentiates Sensitivity to PARP Inhibitor in Biliary Tract Cancer |
title_full_unstemmed | Inhibition of WEE1 Potentiates Sensitivity to PARP Inhibitor in Biliary Tract Cancer |
title_short | Inhibition of WEE1 Potentiates Sensitivity to PARP Inhibitor in Biliary Tract Cancer |
title_sort | inhibition of wee1 potentiates sensitivity to parp inhibitor in biliary tract cancer |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9016294/ https://www.ncbi.nlm.nih.gov/pubmed/34352995 http://dx.doi.org/10.4143/crt.2021.473 |
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