NF-kB signaling mediates acquired resistance after PARP inhibition
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Yuko Nakagawa1,2,*, Anna S. Sedukhina1,*, Naoki Okamoto2, Satoi Nagasawa1,3, Nao Suzuki2, Tomohiko Ohta1, Hiroyoshi Hattori4, Marta Roche-Molina5, Ana J. Narváez6, Anand D. Jeyasekharan7, Juan A. Bernal5, Ko Sato1
1Department of Translational Oncology, St. Marianna University Graduate School of Medicine, Kawasaki 216–8511, Japan
2Department of Obstetrics and Gynecology, St. Marianna University Graduate School of Medicine, Kawasaki 216–8511, Japan
3Division of Breast and Endocrine Surgery, Department of Surgery, St. Marianna University Graduate School of Medicine, Kawasaki 216–8511, Japan
4Laboratory of Advanced Therapy, Department of Hematology and Oncology Research, Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya 460–0001, Japan
5Department of Cardiovascular Development and Repair, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain
6MRC Cancer Unit at the University of Cambridge, Hutchison Research Centre, CB2 0XZ, UK
7Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, 117599, Singapore
*These authors have contributed equally to this work
Ko Sato, e-mail: [email protected]
Received: August 12, 2014 Accepted: December 07, 2014 Published: January 12, 2015
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.
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