| Literature DB >> 29628435 |
Malvika Koundinya1, Judith Sudhalter1, Albane Courjaud2, Bruno Lionne2, Gaetan Touyer2, Luc Bonnet2, Isabelle Menguy2, Isabelle Schreiber2, Christelle Perrault2, Stephanie Vougier2, Brigitte Benhamou2, Bailin Zhang3, Timothy He3, Qiang Gao3, Patricia Gee3, Daniel Simard4, M Paola Castaldi5, Ronald Tomlinson5, Stephan Reiling6, Matthieu Barrague7, Richard Newcombe1, Hui Cao8, Yanjun Wang9, Fangxian Sun9, Joshua Murtie9, Mark Munson7, Eric Yang8, David Harper1, Monsif Bouaboula1, Jack Pollard8, Claudine Grepin2, Carlos Garcia-Echeverria3, Hong Cheng3, Francisco Adrian1, Christopher Winter1, Stuart Licht10, Ivan Cornella-Taracido5, Rosalia Arrebola2, Aaron Morris11.
Abstract
Activating KRAS mutations are major oncogenic drivers in multiple tumor types. Synthetic lethal screens have previously been used to identify targets critical for the survival of KRAS mutant cells, but their application to drug discovery has proven challenging, possibly due in part to a failure of monolayer cultures to model tumor biology. Here, we report the results of a high-throughput synthetic lethal screen for small molecules that selectively inhibit the growth of KRAS mutant cell lines in soft agar. Chemoproteomic profiling identifies the target of the most KRAS-selective chemical series as dihydroorotate dehydrogenase (DHODH). DHODH inhibition is shown to perturb multiple metabolic pathways. In vivo preclinical studies demonstrate strong antitumor activity upon DHODH inhibition in a pancreatic tumor xenograft model.Entities:
Keywords: KRAS mutation; cancer metabolism; chemoproteomics; pyrimidine biosynthesis; synthetic lethality
Mesh：
Substances：
Year: 2018 PMID： 29628435 DOI： 10.1016/j.chembiol.2018.03.005
Source DB: PubMed Journal: Cell Chem Biol ISSN： 2451-9448 Impact factor: 8.116