Inhibition of DHODH Enhances Replication-Associated Genomic Instability and Promotes Sensitivity in Endometrial Cancer

Simple Summary Endometrial cancer is the most common type of cancer that affects the female reproductive organs. Over 50% of women with EC present with early-stage, low-risk disease, and are treated with surgery alone. However, women diagnosed with advanced or recurrent disease have a poor prognosis and they have poor response to current therapies. However, the molecular mechanisms and the prognostic prediction for EC patients remain unclear. In this work, we identified that cancer cells utilize dysregulated nucleotide metabolism to enhance proliferation and progression. We targeted one of the dysregulated genes (DHODH) that is critical for metabolism of nucleotide biosynthesis in endometrial cancer cell. Our results provide potential clinical application to select endometrial cancer patient using "overexpression of dysregulated genes (DHODH) as the genetic markers for tailored therapeutic intervention using repurposed FDA approved drugs (Teriflunomide). Furthermore, it revealed a potential combination therapeutic strategy (Teriflunomide+ Olaparib) for the treatment of "DHODH overexpressing" endometrial cancer. Overall, this result provides preclinical data to establish future clinical therapeutic intervention to increase the efficacy of treatment response that improves overall survival of endometrial cancer patients.Abstract Endometrial carcinoma (EC) is the most common gynecological malignancy in the United States. De novo pyrimidine synthesis pathways generate nucleotides that are required for DNA synthesis. Approximately 38% of human endometrial tumors present with an overexpression of human dihydroorotate dehydrogenase (DHODH). However, the role of DHODH in cancer cell DNA replication and its impact on modulating a treatment response is currently unknown. Here, we report that endometrial tumors with overexpression of DHODH are associated with a high mutation count and chromosomal instability. Furthermore, tumors with an overexpression of DHODH show significant co-occurrence with mutations in DNA replication polymerases, which result in a histologically high-grade endometrial tumor. An in vitro experiment demonstrated that the inhibition of DHODH in endometrial cancer cell lines significantly induced replication-associated DNA damage and hindered replication fork progression. Furthermore, endometrial cancer cells were sensitive to the DHODH inhibitor either alone or in combination with the Poly (ADP-ribose) polymerase 1 inhibitor. Our findings may have important clinical implications for utilizing DHODH as a potential target to enhance cytotoxicity in high-grade endometrial tumors.