title: Mitoxantrone targets human ubiquitin-specific peptidase 11 (USP11) and is a potent inhibitor of pancreatic cancer cell survival.
abstract: Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer-related death in the United States, with a 95% five-year mortality rate. For over a decade, gemcitabine (GEM) has been the established first-line treatment for this disease despite suboptimal response rates. The development of PARP inhibitors that target the DNA damage repair (DDR) system in PDA cells has generated encouraging results. Ubiquitin-specific peptidase 11 (USP11), an enzyme that interacts with the DDR protein BRCA2, was recently discovered to play a key role in DNA double-strand break repair and may be a novel therapeutic target. A systematic high-throughput approach was used to biochemically screen 2,000 U.S. Food and Drug Administration (FDA)-approved compounds for inhibition of USP11 enzymatic activity. Six pharmacologically active small molecules that inhibit USP11 enzymatic activity were identified. An in vitro drug sensitivity assay demonstrated that one of these USP11 inhibitors, mitoxantrone, impacted PDA cell survival with an IC50 of less than 10 nM. Importantly, across six different PDA cell lines, two with defects in the Fanconi anemia/BRCA2 pathway (Hs766T and Capan-1), mitoxantrone is 40- to 20,000-fold more potent than GEM, with increased endogenous USP11 mRNA levels associated with increased sensitivity to mitoxantrone. Interestingly, USP11 silencing in PDA cells also enhanced sensitivity to GEM. These findings establish a preclinical model for the rapid discovery of FDA-approved compounds and identify USP11 as a target of mitoxantrone in PDA.
  
  
  CONCLUSIONS
  This high-throughput approach provides a strong rationale to study mitoxantrone in an early-phase clinical setting for the treatment of PDA.
authors.affiliation: Thomas Jefferson University, 1015 Walnut Street, Curtis 611A, Philadelphia, PA 19107, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Burkhart
authors.forename: Yu
authors.initials: Y
authors.lastname: Peng
authors.forename: Zoë A
authors.initials: ZA
authors.lastname: Norris
authors.forename: Renée M
authors.initials: RM
authors.lastname: Tholey
authors.forename: Vanessa A
authors.initials: VA
authors.lastname: Talbott
authors.forename: Qin
authors.initials: Q
authors.lastname: Liang
authors.forename: Yongxing
authors.initials: Y
authors.lastname: Ai
authors.forename: Kathy
authors.initials: K
authors.lastname: Miller
authors.forename: Shruti
authors.initials: S
authors.lastname: Lal
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Cozzitorto
authors.forename: Agnieska K
authors.initials: AK
authors.lastname: Witkiewicz
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Yeo
authors.forename: Matthew
authors.initials: M
authors.lastname: Gehrmann
authors.forename: Andrew
authors.initials: A
authors.lastname: Napper
authors.forename: Jordan M
authors.initials: JM
authors.lastname: Winter
authors.forename: Janet A
authors.initials: JA
authors.lastname: Sawicki
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Zhuang
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Brody
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D024682:BRCA2 Protein / Q000235:genetics; D001562:Benzimidazoles / Q000627:therapeutic use; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000201:enzymology; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004354:Drug Screening Assays, Antitumor; D020868:Gene Silencing; D057166:High-Throughput Screening Assays; D006801:Humans; D008942:Mitoxantrone / Q000627:therapeutic use*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013869:Thiolester Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D024682:BRCA2 Protein; D001562:Benzimidazoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C101359:USP11 protein, human; C521013:veliparib; D003841:Deoxycytidine; D008942:Mitoxantrone; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D013869:Thiolester Hydrolases; D000093542:Gemcitabine