title: Combination therapy targeting the Chk1 and Wee1 kinases shows therapeutic efficacy in neuroblastoma.
abstract: Neuroblastoma is uniquely sensitive to single-agent inhibition of the DNA damage checkpoint kinase Chk1, leading us to examine downstream effectors of this pathway and identify mitotic regulator Wee1 as an additional therapeutic target in this disease. Wee1 was overexpressed in both neuroblastoma cell lines and high-risk patient tumors. Genetic or pharmacologic abrogation of Wee1 signaling results in marked cytotoxicity in 10 of 11 neuroblastoma cell lines with a median IC(50) of 300 nmol/L for the Wee1-selective small-molecule inhibitor MK-1775. Murine tumor lines derived from mice that were either heterozygous or homozygous for MycN were particularly sensitive to single-agent inhibition of Wee1 (IC(50)s of 160 and 62 nmol/L, respectively). Simultaneous pharmacologic inhibition of Chk1 and Wee1 acted in a synergistic fashion to further impede neuroblastoma cell growth in vitro, in a manner greater than the individual inhibitors either alone or combined with chemotherapy. Combination Chk1 and Wee1 inhibition also revealed in vivo efficacy in neuroblastoma xenografts. Taken together, our results show that neuroblastoma cells depend on Wee1 activity for growth and that inhibition of this kinase may serve as a therapeutic for patients with neuroblastoma.
authors.affiliation: Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Mike R
authors.initials: MR
authors.lastname: Russell
authors.forename: Kirill
authors.initials: K
authors.lastname: Levin
authors.forename: JulieAnn
authors.initials: J
authors.lastname: Rader
authors.forename: Lili
authors.initials: L
authors.lastname: Belcastro
authors.forename: Yimei
authors.initials: Y
authors.lastname: Li
authors.forename: Daniel
authors.initials: D
authors.lastname: Martinez
authors.forename: Bruce
authors.initials: B
authors.lastname: Pawel
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Shumway
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.forename: Kristina A
authors.initials: KA
authors.lastname: Cole
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009447:Neuroblastoma / Q000188:drug therapy*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011494:Protein Kinases / Q000187:drug effects*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D011744:Pyrimidinones; D023041:Xenograft Model Antitumor Assays
chemical_list: D018797:Cell Cycle Proteins; C559815:MK-8776; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; C549567:adavosertib