Dependence on the Pyrimidine Biosynthetic Enzyme DHODH Is a Synthetic Lethal Vulnerability in Mutant KRAS-Driven Cancers
Malvika Koundinya, Judith Sudhalter, Albane Courjaud, Bruno Lionne, Gaetan Touyer, Luc Bonnet, Isabelle Menguy, Isabelle Schreiber, Christelle Perrault, Stephanie Vougier, Brigitte Benhamou, Bailin Zhang, Timothy He, Qiang Gao, Patricia Gee, Daniel Simard, M. Paola Castaldi, Ronald Tomlinson, Stephan Reiling, Matthieu Barrague, Richard Newcombe, Hui Cao, Yanjun Wang, Fangxian Sun, Joshua Murtie, Mark Munson, Eric Yang, David Harper, Monsif Bouaboula, Jack Pollard, Claudine Grepin, Carlos Garcia-Echeverria, Hong Cheng, Francisco Adrian, Christopher Winter, Stuart Licht, Ivan Cornella-Taracido, Rosalia Arrebola, Aaron Morris
Index: 10.1016/j.chembiol.2018.03.005
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Abstract
ActivatingKRASmutations are major oncogenic drivers in multiple tumor types. Synthetic lethal screens have previously been used to identify targets critical for the survival ofKRASmutant 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 ofKRASmutant cell lines in soft agar. Chemoproteomic profiling identifies the target of the mostKRAS-selective chemical series as dihydroorotate dehydrogenase (DHODH). DHODH inhibition is shown to perturb multiple metabolic pathways.In vivopreclinical studies demonstrate strong antitumor activity upon DHODH inhibition in a pancreatic tumor xenograft model.