title: An Unbiased Oncology Compound Screen to Identify Novel Combination Strategies.
abstract: Combination drug therapy is a widely used paradigm for managing numerous human malignancies. In cancer treatment, additive and/or synergistic drug combinations can convert weakly efficacious monotherapies into regimens that produce robust antitumor activity. This can be explained in part through pathway interdependencies that are critical for cancer cell proliferation and survival. However, identification of the various interdependencies is difficult due to the complex molecular circuitry that underlies tumor development and progression. Here, we present a high-throughput platform that allows for an unbiased identification of synergistic and efficacious drug combinations. In a screen of 22,737 experiments of 583 doublet combinations in 39 diverse cancer cell lines using a 4 by 4 dosing regimen, both well-known and novel synergistic and efficacious combinations were identified. Here, we present an example of one such novel combination, a Wee1 inhibitor (AZD1775) and an mTOR inhibitor (ridaforolimus), and demonstrate that the combination potently and synergistically inhibits cancer cell growth in vitro and in vivo This approach has identified novel combinations that would be difficult to reliably predict based purely on our current understanding of cancer cell biology. Mol Cancer Ther; 15(6); 1155-62. ©2016 AACR.
authors.affiliation: Merck Research Laboratories, Boston, Massachusetts. jennifer_oneil@merck.com.
authors.forename: Jennifer
authors.initials: J
authors.lastname: O'Neil
authors.affiliation: Merck Research Laboratories, Boston, Massachusetts.
authors.forename: Yair
authors.initials: Y
authors.lastname: Benita
authors.affiliation: Merck Research Laboratories, Boston, Massachusetts.
authors.forename: Igor
authors.initials: I
authors.lastname: Feldman
authors.affiliation: Merck Research Laboratories, Boston, Massachusetts.
authors.forename: Melissa
authors.initials: M
authors.lastname: Chenard
authors.affiliation: Merck Research Laboratories, Boston, Massachusetts.
authors.forename: Brian
authors.initials: B
authors.lastname: Roberts
authors.affiliation: Merck Research Laboratories, North Wales, Pennsylvania.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Merck Research Laboratories, North Wales, Pennsylvania.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Merck Research Laboratories, Boston, Massachusetts.
authors.forename: Astrid
authors.initials: A
authors.lastname: Kral
authors.affiliation: Merck Research Laboratories, Boston, Massachusetts.
authors.forename: Serguei
authors.initials: S
authors.lastname: Lejnine
authors.affiliation: Merck Research Laboratories, Boston, Massachusetts.
authors.forename: Andrey
authors.initials: A
authors.lastname: Loboda
authors.affiliation: Merck Research Laboratories, Boston, Massachusetts.
authors.forename: William
authors.initials: W
authors.lastname: Arthur
authors.affiliation: Merck Research Laboratories, Boston, Massachusetts.
authors.forename: Razvan
authors.initials: R
authors.lastname: Cristescu
authors.affiliation: Merck Research Laboratories, Boston, Massachusetts.
authors.forename: Brian B
authors.initials: BB
authors.lastname: Haines
authors.affiliation: Merck Research Laboratories, Boston, Massachusetts.
authors.forename: Christopher
authors.initials: C
authors.lastname: Winter
authors.affiliation: Merck Research Laboratories, Boston, Massachusetts.
authors.forename: Theresa
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Merck Research Laboratories, Boston, Massachusetts.
authors.forename: Andrew
authors.initials: A
authors.lastname: Bloecher
authors.affiliation: Merck Research Laboratories, Boston, Massachusetts.
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Shumway
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D004357:Drug Synergism; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D011744:Pyrimidinones; D011897:Random Allocation; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; C515074:ridaforolimus; C549567:adavosertib; D020123:Sirolimus