Please use this identifier to cite or link to this item: https://doi.org/10.18632/oncotarget.2868
Title: NF-κB signaling mediates acquired resistance after PARP inhibition
Authors: Nakagawa, Y
Sedukhina, A.S
Okamoto, N
Nagasawa, S
Suzuki, N
Ohta, T
Hattori, H
Roche-Molina, M
Narváez, A.J
Jeyasekharan, A.D 
Bernal, J.A
Sato, K
Keywords: 3 (4 methylphenylsulfonyl) 2 propenenitrile
bortezomib
immunoglobulin enhancer binding protein
nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase
olaparib
RNA
rucaparib
immunoglobulin enhancer binding protein
nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase inhibitor
Article
cell death
controlled study
drug sensitivity
enzyme inhibition
gene expression
human
human cell
ovary cell
RNA sequence
signal transduction
upregulation
antagonists and inhibitors
apoptosis
Breast Neoplasms
drug effects
drug resistance
female
genetics
metabolism
nucleotide sequence
Ovarian Neoplasms
pathology
signal transduction
tumor cell line
tumor suppressor gene
Apoptosis
Base Sequence
Bortezomib
Breast Neoplasms
Cell Line, Tumor
Drug Resistance, Neoplasm
Female
Genes, BRCA1
Humans
NF-kappa B
Ovarian Neoplasms
Poly(ADP-ribose) Polymerase Inhibitors
Signal Transduction
Up-Regulation
Issue Date: 2015
Citation: Nakagawa, Y, Sedukhina, A.S, Okamoto, N, Nagasawa, S, Suzuki, N, Ohta, T, Hattori, H, Roche-Molina, M, Narváez, A.J, Jeyasekharan, A.D, Bernal, J.A, Sato, K (2015). NF-κB signaling mediates acquired resistance after PARP inhibition. Oncotarget 6 (6) : 3825-3839. ScholarBank@NUS Repository. https://doi.org/10.18632/oncotarget.2868
Rights: Attribution 4.0 International
Abstract: PARP inhibitors are a class of promising anti-cancer drugs, with proven activity in BRCA mutant cancers. However, as with other targeted agents, treatment with PARP inhibitors generates acquired resistance within these tumors. The mechanism of this acquired resistance is poorly understood. We established cell lines that are resistant to PARP inhibitor by continuous treatment with the drug, and then used RNA sequencing to compare gene expression. Pathway analysis on the RNA sequencing data indicates that NF-κB signaling is preferentially up-regulated in PARP inhibitorresistant cells, and that knockdown of core components in NF-κB signaling reverses the sensitivity to PARP inhibitor in resistant cells. Of therapeutic relevance, we show that PARP inhibitor-resistant cells are sensitive to an NF-κB inhibitor in comparison to their parental controls. Malignancies with up-regulation of NF-κB are sensitive to bortezomib, a proteasome inhibitor that is currently used in the clinic. We also show that treatment with bortezomib results in cell death in the PARP inhibitor-resistant cells, but not in parental cells. Therefore we propose that up-regulation of NF-κB signaling is a key mechanism underlying acquired resistance to PARP inhibition, and that NF-κB inhibition, or bortezomib are potentially effective anti-cancer agents after the acquisition of resistance to PARP inhibitors.
Source Title: Oncotarget
URI: https://scholarbank.nus.edu.sg/handle/10635/180961
ISSN: 19492553
DOI: 10.18632/oncotarget.2868
Rights: Attribution 4.0 International
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