title: Pharmacological abrogation of S-phase checkpoint enhances the anti-tumor activity of gemcitabine in vivo.
abstract: Chk1 and Chk2 kinases are critically involved in modulating DNA damage checkpoints. In particular, Chk1, a key activator of the S-phase DNA damage response, may be involved in resistance to genotoxic therapies that target DNA synthesis. We studied the in vitro and in vivo effects of EXEL-9844 (XL844), a potent, orally available, and specific inhibitor of Chk1 and Chk2, in combination with gemcitabine. In clonogenic assays using multiple cell lines in vitro, EXEL-9844 had only minor effects as a single agent but substantially enhanced gemcitabine-induced cell killing. Correspondingly, in PANC-1 cells, EXEL-9844 increased gemcitabine-induced H2AX phosphorylation, blocked Cdc25A phosphorylation, and induced premature mitotic entry. In a PANC-1 xenograft model, EXEL-9844 significantly enhanced gemcitabine antitumor activity but had limited effect as a single agent. Together, these data show that cell cycle checkpoint inhibitors may have significant clinical utility in potentiating the activity of gemcitabine.
authors.affiliation: Exelixis Inc., South San Francisco, California 94083, USA. matthews@exelixis.com
authors.forename: David J
authors.initials: DJ
authors.lastname: Matthews
authors.forename: F Michael
authors.initials: FM
authors.lastname: Yakes
authors.forename: Jason
authors.initials: J
authors.lastname: Chen
authors.forename: Michele
authors.initials: M
authors.lastname: Tadano
authors.forename: Lester
authors.initials: L
authors.lastname: Bornheim
authors.forename: Douglas O
authors.initials: DO
authors.lastname: Clary
authors.forename: Albert
authors.initials: A
authors.lastname: Tai
authors.forename: Jill M
authors.initials: JM
authors.lastname: Wagner
authors.forename: Nicole
authors.initials: N
authors.lastname: Miller
authors.forename: Yong D
authors.initials: YD
authors.lastname: Kim
authors.forename: Scott
authors.initials: S
authors.lastname: Robertson
authors.forename: Louis
authors.initials: L
authors.lastname: Murray
authors.forename: Larry M
authors.initials: LM
authors.lastname: Karnitz
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002478:Cells, Cultured; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D018816:Genes, cdc / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016196:S Phase / Q000187:drug effects* / Q000502:physiology; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D000093542:Gemcitabine