Supplementary Figure S2 from Combinatorial Screening of Pancreatic Adenocarcinoma Reveals Sensitivity to Drug Combinations Including Bromodomain Inhibitor Plus Neddylation Inhibitor
journal contribution
posted on 2023-04-03, 16:01 authored by Casey G. Langdon, James T. Platt, Robert E. Means, Pinar Iyidogan, Ramanaiah Mamillapalli, Michael Klein, Matthew A. Held, Jong Woo Lee, Ja Seok Koo, Christos Hatzis, Howard S. Hochster, David F. SternHeatmap of hierarchical clustering of normalized AUC and hierarchical clustering of cell lines
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Hixon Foundation
Connecticut Department of Public Health
NIH
Yale Center for Molecular Discovery
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ARTICLE 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 activating KRAS mutations, 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 inhibited in vivo growth of PDAC cell line xenografts. Overall, this work revealed novel combinatorial regimens, including JQ1 plus MLN4294, which show promise for the treatment of RAS-driven PDAC. Mol Cancer Ther; 16(6); 1041–53. ©2017 AACR.Usage metrics
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CarcinogenesisSignal transductionCell CycleSignal transduction pathwaysChemotherapyBiochemical modulators of the therapeutic indexCombination chemotherapyDrug Discovery TechnologiesScreening strategies (assays and chemical libraries)Drug TargetsOncoprotein & tumor suppressor drug targetsGastrointestinal CancersPancreatic cancerGenome BiologyStructural genomicsPharmacologyCellular pharmacologyPharmacogenetics/pharmacogenomics
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