title: Proteasome inhibitors block DNA repair and radiosensitize non-small cell lung cancer.
abstract: Despite optimal radiation therapy (RT), chemotherapy and/or surgery, a majority of patients with locally advanced non-small cell lung cancer (NSCLC) fail treatment. To identify novel gene targets for improved tumor control, we performed whole genome RNAi screens to identify knockdowns that most reproducibly increase NSCLC cytotoxicity. These screens identified several proteasome subunits among top hits, including the topmost hit PSMA1, a component of the core 20 S proteasome. Radiation and proteasome inhibition showed synergistic effects. Proteasome inhibition resulted in an 80-90% decrease in homologous recombination (HR), a 50% decrease in expression of NF-κB-inducible HR genes BRCA1 and FANCD2, and a reduction of BRCA1, FANCD2 and RAD51 ionizing radiation-induced foci. IκBα RNAi knockdown rescued NSCLC radioresistance. Irradiation of mice with NCI-H460 xenografts after inducible PSMA1 shRNA knockdown markedly increased murine survival compared to either treatment alone. Proteasome inhibition is a promising strategy for NSCLC radiosensitization via inhibition of NF-κB-mediated expression of Fanconi Anemia/HR DNA repair genes.
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Cron
authors.forename: Kaya
authors.initials: K
authors.lastname: Zhu
authors.forename: Deepa S
authors.initials: DS
authors.lastname: Kushwaha
authors.forename: Grace
authors.initials: G
authors.lastname: Hsieh
authors.forename: Dmitry
authors.initials: D
authors.lastname: Merzon
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rameseder
authors.forename: Clark C
authors.initials: CC
authors.lastname: Chen
authors.forename: Alan D
authors.initials: AD
authors.lastname: D'Andrea
authors.forename: David
authors.initials: D
authors.lastname: Kozono
mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D003131:Combined Modality Therapy; D004260:DNA Repair / Q000235:genetics*; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000235:genetics* / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D034622:RNA Interference; D051135:Rad51 Recombinase / Q000235:genetics; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D011878:Radiotherapy / Q000379:methods; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
chemical_list: D019313:BRCA1 Protein; D001897:Boronic Acids; D052236:Fanconi Anemia Complementation Group D2 Protein; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D021122:Protein Subunits; D011719:Pyrazines; D011838:Radiation-Sensitizing Agents; D000069286:Bortezomib; D051135:Rad51 Recombinase; C000589188:PSMA1 protein, human; D046988:Proteasome Endopeptidase Complex
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