title: NF-κB signaling mediates acquired resistance after PARP inhibition.
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 inhibitor-resistant 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.
authors: Department of Translational Oncology, St. Marianna University Graduate School of Medicine, Kawasaki 216-8511, Japan.|Department of Obstetrics and Gynecology, St. Marianna University Graduate School of Medicine, Kawasaki 216-8511, Japan.
authors: Yuko
authors: Y
authors: Nakagawa
authors: Department of Translational Oncology, St. Marianna University Graduate School of Medicine, Kawasaki 216-8511, Japan.
authors: Anna S
authors: AS
authors: Sedukhina
authors: Department of Obstetrics and Gynecology, St. Marianna University Graduate School of Medicine, Kawasaki 216-8511, Japan.
authors: Naoki
authors: N
authors: Okamoto
authors: Department of Translational Oncology, St. Marianna University Graduate School of Medicine, Kawasaki 216-8511, Japan.|Division of Breast and Endocrine Surgery, Department of Surgery, St. Marianna University Graduate School of Medicine, Kawasaki 216-8511, Japan.
authors: Satoi
authors: S
authors: Nagasawa
authors: Department of Obstetrics and Gynecology, St. Marianna University Graduate School of Medicine, Kawasaki 216-8511, Japan.
authors: Nao
authors: N
authors: Suzuki
authors: Department of Translational Oncology, St. Marianna University Graduate School of Medicine, Kawasaki 216-8511, Japan.
authors: Tomohiko
authors: T
authors: Ohta
authors: Laboratory of Advanced Therapy, Department of Hematology and Oncology Research, Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya 460-0001, Japan.
authors: Hiroyoshi
authors: H
authors: Hattori
authors: Department of Cardiovascular Development and Repair, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain.
authors: Marta
authors: M
authors: Roche-Molina
authors: MRC Cancer Unit at the University of Cambridge, Hutchison Research Centre, CB2 0XZ, UK.
authors: Ana J
authors: AJ
authors: Narváez
authors: Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, 117599, Singapore.
authors: Anand D
authors: AD
authors: Jeyasekharan
authors: Department of Cardiovascular Development and Repair, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain.
authors: Juan A
authors: JA
authors: Bernal
authors: Department of Translational Oncology, St. Marianna University Graduate School of Medicine, Kawasaki 216-8511, Japan.
authors: Ko
authors: K
authors: Sato
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D000069286:Bortezomib / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D019398:Genes, BRCA1; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D016328:NF-kappa B; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D000069286:Bortezomib