TDP1 and TOP1 modulation in Olaparib-resistant cancer determines the efficacy of subsequent chemotherapy

Jin Won Kim, Ahrum Min, Seock Ah Im, Hyemin Jang, Yu Jin Kim, Hee Jun Kim, Kyung Hun Lee, Tae Yong Kim, Keun Wook Lee, Do Youn Oh, Jee Hyun Kim, Yung Jue Bang

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Abstract

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.

Original languageEnglish
Article number334
JournalCancers
Volume12
Issue number2
DOIs
StatePublished - 3 Feb 2020

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Keywords

  • Carryover effect
  • Irinotecan
  • Olaparib
  • TDP1
  • TOP1 activity

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