title: Identification of preferred chemotherapeutics for combining with a CHK1 inhibitor.
abstract: Here we report that GNE-783, a novel checkpoint kinase-1 (CHK1) inhibitor, enhances the activity of gemcitabine by disabling the S- and G2 cell-cycle checkpoints following DNA damage. Using a focused library of 51 DNA-damaging agents, we undertook a systematic screen using three different cell lines to determine which chemotherapeutics have their activity enhanced when combined with GNE-783. We found that GNE-783 was most effective at enhancing activity of antimetabolite-based DNA-damaging agents; however, there was a surprisingly wide range of activity within each class of agents. We, next, selected six different therapeutic agents and screened these in combination with GNE-783 across a panel of cell lines. This revealed a preference for enhanced chemopotentiation of select agents within tumor types, as, for instance, GNE-783 preferentially enhanced the activity of temozolomide only in melanoma cell lines. Additionally, although p53 mutant status was important for the overall response to combinations with some agents; our data indicate that this alone was insufficient to predict synergy. We finally compared the ability of a structurally related CHK1 inhibitor, GNE-900, to enhance the in vivo activity of gemcitabine, CPT-11, and temozolomide in xenograft models. GNE-900 significantly enhanced activity of only gemcitabine in vivo, suggesting that strong chemopotentiation in vitro can translate into chemopotentiation in vivo. In conclusion, our results show that selection of an appropriate agent to combine with a CHK1 inhibitor needs to be carefully evaluated in the context of the genetic background and tumor type in which it will be used.
authors.affiliation: Corresponding Author: Thomas O'Brien, Department of Translational Oncology, Genentech, 1 DNA Way, South San Francisco, CA 94080. obrien.tom@gene.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xiao
authors.forename: Judi
authors.initials: J
authors.lastname: Ramiscal
authors.forename: Kaska
authors.initials: K
authors.lastname: Kowanetz
authors.forename: Christopher
authors.initials: C
authors.lastname: Del Nagro
authors.forename: Shiva
authors.initials: S
authors.lastname: Malek
authors.forename: Marie
authors.initials: M
authors.lastname: Evangelista
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Blackwood
authors.forename: Peter K
authors.initials: PK
authors.lastname: Jackson
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Brien
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D002243:Carbolines / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D004249:DNA Damage / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D045325:HCT116 Cells; D019073:HT29 Cells; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009374:Neoplasms, Experimental; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D000077204:Temozolomide; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: C588399:3-(4-(1-piperidinylmethyl)phenyl)-9H-pyrrolo(2,3-b-5,4-c')dipyridine-6-carbonitrile; D000970:Antineoplastic Agents; D002243:Carbolines; C000589252:GNE-783; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011758:Pyrroles; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D003841:Deoxycytidine; D000077146:Irinotecan; D003606:Dacarbazine; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; D002166:Camptothecin; D000077204:Temozolomide; D000093542:Gemcitabine