Object's details: Targeted inhibition of the ATR/CHK1 pathway overcomes resistance to olaparib and dysregulates DNA damage response protein expression in BRCA2MUT ovarian cancer cells, Sonata Bis 2019/34/E/NZ7/00056, Sonata Bis-9 (dataset)

Provider:Repozytorium Uniwersytetu Łódzkiego

Description

Title:
Targeted inhibition of the ATR/CHK1 pathway overcomes resistance to olaparib and dysregulates DNA damage response protein expression in BRCA2MUT ovarian cancer cells, Sonata Bis 2019/34/E/NZ7/00056, Sonata Bis-9 (dataset)
Creator:
Rogalska, Aneta
Contributor:
Department of Medical Biophysics, Institute of Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 141/143 Pomorska Street, 90-236, Lodz, Poland.;
aneta.rogalska@biol.uni.lodz.pl
Description:
Olaparib is a PARP inhibitor (PARPi) approved for targeted treatment of ovarian cancer (OC). However, its efficacy is impeded by the inevitable occurrence of resistance. This study investigated whether the cytotoxic activity of olaparib could be synergistically enhanced in olaparib-resistant OC cells with BRCA2 reversion mutation by the addition of inhibitors of the ATR/CHK1 pathway. Moreover, this study provide insights into alterations in the DNA damage response (DDR) pathway induced by combination treatments. Antitumor activity of olaparib alone or combined with an ATR inhibitor (ATRi, ceralasertib) or CHK1 inhibitor (CHK1i, MK-8776) was evaluated in OC cell lines sensitive (PEO1, PEO4) and resistant (PEO1-OR) to olaparib. Antibody microarrays were used to explore changes in expression of 27 DDR-related proteins. Olaparib in combination with ATR/CHK1 inhibitors synergistically induced a decrease in viability and clonogenic survival and an increase in apoptosis mediated by caspase-3/7 in all OC cells. Combination treatments induced cumulative alterations in expression of DDR-related proteins mediating distinct DNA repair pathways and cell cycle control. In the presence of ATRi and CHK1i, olaparib-induced upregulation of proteins determining cell fate after DNA damage (PARP1, CHK1, c-Abl, Ku70, Ku80, MDM2, and p21) was abrogated in PEO1-OR cells. Overall, the addition of ATRi or CHK1i to olaparib effectively overcomes resistance to PARPi exerting anti-proliferative effect in BRCA2MUT olaparib-resistant OC cells and alters expression of DDR-related proteins. These new molecular insights into cellular response to olaparib combined with ATR/CHK1 inhibitors might help improve targeted therapies for olaparib-resistant OC.;
This work was supported by the National Science Centre, Poland (Project grant number: Sonata Bis 2019/34/E/NZ7/00056).
Object availability:
free access
Rights:
Uznanie autorstwa 4.0 Międzynarodowe;
http://creativecommons.org/licenses/by/4.0
Date:
2024.03.07;
2023
Type:
Dataset
Language:
English
Format:
application/octet-stream
Subject:
ATR inhibitor;
CHK1 inhibitor;
PARP inhibitor;
targeted therapy;
overcomes resistance;
ovarian cancer
Identifier: http://hdl.handle.net/11089/50733
Data provider:
Repozytorium Uniwersytetu Łódzkiego

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Object's details: Targeted inhibition of the ATR/CHK1 pathway overcomes resistance to olaparib and dysregulates DNA damage response protein expression in BRCA2MUT ovarian cancer cells, Sonata Bis 2019/34/E/NZ7/00056, Sonata Bis-9 (dataset)

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