Dependence on the Pyrimidine Biosynthetic Enzyme DHODH Is a Synthetic Lethal Vulnerability in Mutant KRAS-Driven Cancers

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.

Reactivation of Dihydroorotate Dehydrogenase-Driven Pyrimidine Biosynthesis Restores Tumor Growth of Respiration-Deficient Cancer Cells

“…In our experimental models, the pathway, including DHODH itself, was primed to respond when the block in CoQ redox-cycling was removed. Inhibitors of DHODH are used in the clinic as anti-rheumatics (Olsen and Stein, 2004) and show efficacy in cancer settings either alone or in combination with anti-cancer agents (Brown et al, 2017;Mathur et al, 2017;Sykes et al, 2016;Shukla et al, 2017;Kim et al, 2017;Koundinya et al, 2018). A more effective therapeutic approach could involve intervention at the level of respiratory CIII.…”

Predictive Signatures Inform the Effective Repurposing of Decitabine to Treat KRAS–Dependent Pancreatic Ductal Adenocarcinoma

“…Instead, we demonstrated that the impairment of pyrimidine biosynthesis was responsible for the selective response to decitabine in dep-PDAC. It has been previously recognized that oncogenic KRAS induced metabolic rewiring of nucleotide metabolism (10,41). During the preparation of this manuscript, it was shown that the maintenance of the nucleotides pool via pyrimidine biosynthesis was indeed part of a metabolic reprogramming of KRAS dependency in PDAC and that the inhibition of KRAS-dep signaling led to a selective reduction of pyrimidine metabolites.…”

“…4E). Given the ability for both gemcitabine and decitabine to interfere with nucleotide metabolism and dNTPs pool homeostasis (31)(32)(33), and because the inhibition of pyrimidine biosynthetic enzymes showed a synthetic lethal vulnerability in mutant KRAS-driven cancers (10,41,42) we hypothesized that decitabine might affect dep-PDAC viability based on interfering with nucleotide metabolism. To directly address this hypothesis, we performed an untargeted LC/MS-based metabolomics analysis of polar metabolites isolated from both dep-and indep-PDAC cells upon treatment with decitabine.…”

Cross-Cancer Pleiotropic Associations with Lung Cancer Risk in African Americans

“…DHODH has also been investigated for a role in cancer, including melanoma (58) and acute myeloid leukemia (59), and decreased expression of DHODH was associated with breast cancer risk (60). Several other studies have examined the utility of DHODH inhibitors in cancer by inducing cell-cycle arrest and apoptosis in cancer cells (59,(61)(62)(63)(64)(65)(66). Although DHODH has not been previously associated with lung cancer risk, the abundance of biological evidence for its pleiotropic role in cancer gives credibility to the association.…”