title: Combinatorial Screening of Pancreatic Adenocarcinoma Reveals Sensitivity to Drug Combinations Including Bromodomain Inhibitor Plus Neddylation Inhibitor.
abstract: Pancreatic adenocarcinoma (PDAC) is the fourth most common cause of cancer-related death in the United States. PDAC is difficult to manage effectively, with a five-year survival rate of only 5%. PDAC is largely driven by activatingKRASmutations, and as such, cannot be directly targeted with therapeutic agents that affect the activated protein. Instead, inhibition of downstream signaling and other targets will be necessary to effectively manage PDAC. Here, we describe a tiered single-agent and combination compound screen to identify targeted agents that impair growth of a panel of PDAC cell lines. Several of the combinations identified from the screen were further validated for efficacy and mechanism. Combination of the bromodomain inhibitor JQ1 and the neddylation inhibitor MLN4294 altered the production of reactive oxygen species in PDAC cells, ultimately leading to defects in the DNA damage response. Dual bromodomain/neddylation blockade inhibitedin vivogrowth of PDAC cell line xenografts. Overall, this work revealed novel combinatorial regimens, including JQ1 plus MLN4294, which show promise for the treatment ofRAS-driven PDAC.Mol Cancer Ther; 16(6); 1041-53. ©2017 AACR.
authors.affiliation: Department of Pathology and Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Casey G
authors.initials: CG
authors.lastname: Langdon
authors.affiliation: Department of Pathology and Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut.
authors.forename: James T
authors.initials: JT
authors.lastname: Platt
authors.affiliation: Department of Pathology and Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Means
authors.affiliation: Department of Pathology and Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Pinar
authors.initials: P
authors.lastname: Iyidogan
authors.affiliation: Department of Pathology and Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Ramanaiah
authors.initials: R
authors.lastname: Mamillapalli
authors.affiliation: Department of Pathology and Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut.|Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut.
authors.forename: Michael
authors.initials: M
authors.lastname: Klein
authors.affiliation: Department of Pathology and Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Held
authors.affiliation: Department of Internal Medicine and Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Jong Woo
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine and Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Ja Seok
authors.initials: JS
authors.lastname: Koo
authors.affiliation: Department of Internal Medicine and Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Christos
authors.initials: C
authors.lastname: Hatzis
authors.affiliation: Department of Internal Medicine and Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Howard S
authors.initials: HS
authors.lastname: Hochster
authors.affiliation: Department of Pathology and Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut. df.stern@yale.edu.
authors.forename: David F
authors.initials: DF
authors.lastname: Stern
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D004357:Drug Synergism; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D058990:Molecular Targeted Therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D013481:Superoxides; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004338:Drug Combinations; D013481:Superoxides; D000255:Adenosine Triphosphate