NF-κB signaling mediates acquired resistance after PARP inhibition
Nakagawa, Y Sedukhina, A.S Okamoto, N Nagasawa, S Suzuki, N Ohta, T Hattori, H Roche-Molina, M Narváez, A.J Jeyasekharan, A.D
Nakagawa, Y
Sedukhina, A.S
Okamoto, N
Nagasawa, S
Suzuki, N
Ohta, T
Hattori, H
Roche-Molina, M
Narváez, A.J
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Alternative Title
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.
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
Source Title
Oncotarget
Publisher
Series/Report No.
Collections
Rights
Attribution 4.0 International
Date
2015
DOI
10.18632/oncotarget.2868
Type
Article