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oai:repisalud.isciii.es:20.500.12105/55122024-09-27T09:59:14Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605
Repisalud author Nakagawa, Yuko author Sedukhina, Anna S. author Okamoto, Naoki author Nagasawa, Satoi author Suzuki, Nao author Ohta, Tomohiko author Hattori, Hiroyoshi author Roche-Molina, Marta author Narvaez, Ana J. author Jeyasekharan, Anand D. author Bernal, Juan Antonio author Sato, Ko funder St. Marianna University 2017-12-01T07:37:25Z 2017-12-01T07:37:25Z 2015 Oncotarget. 2015; 6(6):3825-39 1949-2553 Oncotarget 25686825 http://hdl.handle.net/20.500.12105/5512 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-kappa B signaling is preferentially up-regulated in PARP inhibitor-resistant cells, and that knockdown of core components in NF-kappa B 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-kappa B inhibitor in comparison to their parental controls. Malignancies with up-regulation of NF-kappa B 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-kappa B signaling is a key mechanism underlying acquired resistance to PARP inhibition, and that NF-kappa B inhibition, or bortezomib are potentially effective anti-cancer agents after the acquisition of resistance to PARP inhibitors. eng MULTIPLE-MYELOMA CELLS POLY(ADP-RIBOSE) POLYMERASE THERAPY CANCER OLAPARIB ACTIVATION EXPRESSION APOPTOSIS PATHWAY TARGET NF-kappa B signaling mediates acquired resistance after PARP inhibition journal article URL https://repisalud.isciii.es/bitstreams/ab776563-3a2e-4fde-b3e1-cb25e232d267/download File MD5 76af4109decec16a01701aec9100b869 2293052 application/pdf NF-κBSignalingMediatesAcquired_2015 URL https://repisalud.isciii.es/bitstreams/e4fe2b40-7758-4008-9cf3-55ffc7808a26/download File MD5 54d0274c5bd76d8e6d6881a7132f61ee 3885317 application/pdf NF-κBSignalingMediatesAcquired_2015_Supp URL https://repisalud.isciii.es/bitstreams/d6647ef1-028d-429d-a926-614eab807742/download File MD5 65821e3ab37711d1d4416024cd5dc66d 51597 text/plain NF-κBSignalingMediatesAcquired_2015.txt URL https://repisalud.isciii.es/bitstreams/797639e5-8610-41e0-b774-b5436e99016e/download File MD5 1ebd122af6dedd8bc98b329a870a31e3 6767 text/plain NF-κBSignalingMediatesAcquired_2015_Supp.txt URL https://repisalud.isciii.es/bitstreams/d09a1cba-77a3-4fb6-88e9-18fd52d5212c/download File MD5 65821e3ab37711d1d4416024cd5dc66d 51597 text/plain NF-κBSignalingMediatesAcquired_2015.txt URL https://repisalud.isciii.es/bitstreams/76d76e3a-6605-4411-9c11-d6976a1c2467/download File MD5 1ebd122af6dedd8bc98b329a870a31e3 6767 text/plain NF-κBSignalingMediatesAcquired_2015_Supp.txt