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Article

TDP1 and TOP1 Modulation in Olaparib-Resistant Cancer Determines the Efficacy of Subsequent Chemotherapy

by 1,2,3,†, 4,5,†, 1,3,4,5,6,*, 4, 4, 7, 1,4,5,6, 1,4,5,6, 1,2, 1,3,4,5,6, 1,2,3 and 1,4,5,6
1
Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Korea
2
Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam 13620, Korea
3
Translational Medicine, Seoul National University College of Medicine, Seoul 03080, Korea
4
Cancer Research Institute, Seoul National University, Seoul 03080, Korea
5
Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Korea
6
Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, Seoul 03080, Korea
7
Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul 06973, Korea
*
Author to whom correspondence should be addressed.
Jin Won Kim and Ahrum Min contributed equally to this work as co-first authors.
Cancers 2020, 12(2), 334; https://doi.org/10.3390/cancers12020334
Received: 31 December 2019 / Revised: 31 January 2020 / Accepted: 31 January 2020 / Published: 3 February 2020
(This article belongs to the Special Issue PARPs, PAR and NAD Metabolism and Their Inhibitors in Cancer)
The aim of this study was to elucidate the carryover effect of olaparib to subsequent chemotherapy and its underlying mechanisms. We generated olaparib-resistant SNU-484, SNU-601, SNU-668, and KATO-III gastric cancer cell lines and confirmed their resistance by cell viability and colony forming assays. Notably, olaparib-resistant cell lines displayed cross-resistance to cisplatin except for KATO-III. Inversely, olaparib-resistant SNU-484, SNU-668, and KATO-III were more sensitive to irinotecan than their parental cells. However, sensitivity to paclitaxel remained unaltered. There were compensatory changes in the ATM/ATR axis and p-Chk1/2 protein expression. ERCC1 was also induced in olaparib-resistant SNU-484, SNU-601, and SNU-668, which showed cross-resistance to cisplatin. Olaparib-resistant cells showed tyrosyl-DNA phosphodiesterase 1 (TDP1) downregulation with higher topoisomerase 1 (TOP1) activity, which is a target of irinotecan. These changes of TOP1 and TDP1 in olaparib-resistant cells was confirmed as the underlying mechanism for increased irinotecan sensitivity through manipulated gene expression of TOP1 and TDP1 by specific plasmid transfection and siRNA. The patient-derived xenograft model established from the patient who acquired resistance to olaparib with BRCA2 mutation showed increased sensitivity in irinotecan. In conclusion, the carryover effects of olaparib to improve antitumor effect of subsequent irinotecan were demonstrated. These effects should be considered when determining the subsequent therapy with olaparib. View Full-Text
Keywords: olaparib; carryover effect; TOP1 activity; TDP1; irinotecan olaparib; carryover effect; TOP1 activity; TDP1; irinotecan
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MDPI and ACS Style

Kim, J.W.; Min, A.; Im, S.-A.; Jang, H.; Kim, Y.J.; Kim, H.-J.; Lee, K.-H.; Kim, T.-Y.; Lee, K.W.; Oh, D.-Y.; Kim, J.-H.; Bang, Y.-J. TDP1 and TOP1 Modulation in Olaparib-Resistant Cancer Determines the Efficacy of Subsequent Chemotherapy. Cancers 2020, 12, 334. https://doi.org/10.3390/cancers12020334

AMA Style

Kim JW, Min A, Im S-A, Jang H, Kim YJ, Kim H-J, Lee K-H, Kim T-Y, Lee KW, Oh D-Y, Kim J-H, Bang Y-J. TDP1 and TOP1 Modulation in Olaparib-Resistant Cancer Determines the Efficacy of Subsequent Chemotherapy. Cancers. 2020; 12(2):334. https://doi.org/10.3390/cancers12020334

Chicago/Turabian Style

Kim, Jin W., Ahrum Min, Seock-Ah Im, Hyemin Jang, Yu J. Kim, Hee-Jun Kim, Kyung-Hun Lee, Tae-Yong Kim, Keun W. Lee, Do-Youn Oh, Jee-Hyun Kim, and Yung-Jue Bang. 2020. "TDP1 and TOP1 Modulation in Olaparib-Resistant Cancer Determines the Efficacy of Subsequent Chemotherapy" Cancers 12, no. 2: 334. https://doi.org/10.3390/cancers12020334

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