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

Jin Won Kim1,2,3, Ahrum Min4,5, Seock-Ah Im1,3,4,5,6

  • 1Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Korea.

Cancers
|February 8, 2020
PubMed

Insights

Olaparib resistance in gastric cancer cells unexpectedly enhances sensitivity to irinotecan chemotherapy. This carryover effect, driven by changes in TOP1 and TDP1, improves antitumor outcomes and should guide subsequent treatment decisions.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Olaparib, a PARP inhibitor, is used in cancer treatment.
  • Understanding acquired resistance mechanisms is crucial for optimizing therapy.
  • Carryover effects of prior treatments can influence subsequent drug efficacy.

Purpose of the Study:

  • To investigate the carryover effect of olaparib on subsequent chemotherapy in gastric cancer.
  • To elucidate the molecular mechanisms underlying olaparib resistance and cross-resistance.
  • To evaluate the impact of olaparib resistance on sensitivity to other chemotherapeutic agents.

Main Methods:

  • Generation and characterization of olaparib-resistant gastric cancer cell lines (SNU-484, SNU-601, SNU-668, KATO-III).
  • Cell viability, colony formation, and drug sensitivity assays.
  • Analysis of key proteins in DNA damage response pathways (ATM/ATR, p-Chk1/2, ERCC1) and enzymes (TOP1, TDP1).
  • Gene expression manipulation using plasmid transfection and siRNA; validation in patient-derived xenograft models.

Main Results:

  • Olaparib-resistant cells showed cross-resistance to cisplatin but increased sensitivity to irinotecan.
  • Mechanisms included TDP1 downregulation and increased TOP1 activity in resistant cells.
  • ATM/ATR axis and ERCC1 expression were altered, correlating with cisplatin cross-resistance.
  • Patient-derived xenografts from olaparib-resistant patients demonstrated enhanced irinotecan sensitivity.

Conclusions:

  • Acquired olaparib resistance in gastric cancer confers sensitivity to irinotecan.
  • This carryover effect is mediated by alterations in TOP1 and TDP1.
  • Findings suggest a potential therapeutic strategy of using irinotecan after olaparib treatment.
  • Clinical decisions regarding sequential therapy should consider these observed carryover effects.
Keywords:
TDP1TOP1 activitycarryover effectirinotecanolaparib

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