Supplementary Figure S1 from PTEN Regulates Glutamine Flux to Pyrimidine Synthesis and Sensitivity to Dihydroorotate Dehydrogenase Inhibition

Mathur, Deepti; Στρατικόπουλος, Ηλίας; Öztürk, Savaş; Steinbach, Nicole; Pegno, Sarah; Schoenfeld, Sarah; Yong, Raymund L.; Murty, Vundavalli V.; Asara, John M.; Cantley, Lewis C.; Parsons, Ramon

doi:10.1158/2159-8290.22532090.v1

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“…Dihydroorotate dehydrogenase (DHODH) catalyzes the fourth step in this pathway and is essential for de novo pyrimidine synthesis. DHODH inhibitors have shown robust preclinical anticancer activity across diverse cancer types [4][5][6][7][8][9][10][11][12][13] and have recently entered clinical trials for multiple hematologic cancers (NCT04609826 and NCT02509052). Although there is a vast literature on DHODH inhibitors dating back to the early 1990s, and despite the "rediscovery" of DHODH in recent years as a critical cancer cell metabolic dependency, important questions about the cellular response to DHODH inhibition remain unanswered.…”

Section: Introductionmentioning

confidence: 99%

DHODH inhibition enhances the efficacy of immune checkpoint blockade by increasing cancer cell antigen presentation

Mullen

Shukla

Thakur

et al. 2023

Preprint

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Pyrimidine nucleotide biosynthesis is a druggable metabolic dependency of cancer cells, and chemotherapy agents targeting pyrimidine metabolism are the backbone of treatment for many cancers. Dihydroorotate dehydrogenase (DHODH) is an essential enzyme in the de novo pyrimidine biosynthesis pathway that can be targeted by clinically approved inhibitors. However, despite robust preclinical anticancer efficacy, DHODH inhibitors have shown limited single-agent efficacy in phase I clinical trials. Therefore, novel combination therapy strategies are necessary to realize the potential of these drugs. To search for therapeutic vulnerabilities induced by DHODH inhibition, we examined gene expression changes in cancer cells treated with the potent and selective DHODH inhibitor brequinar (BQ). This revealed that BQ treatment causes upregulation of antigen presentation pathway genes and cell surface MHC class I expression. Mechanistic studies showed that this effect is 1) strictly dependent on pyrimidine nucleotide depletion, 2) independent of canonical antigen presentation pathway transcriptional regulators, and 3) mediated by RNA polymerase II elongation control by positive transcription elongation factor B (P-TEFb). Furthermore, BQ showed impressive single-agent efficacy in the immunocompetent B16F10 melanoma model, and combination treatment with BQ and dual immune checkpoint blockade (anti-CTLA-4 plus anti-PD-1) significantly prolonged mouse survival compared to either therapy alone. Our results have important implications for the clinical development of DHODH inhibitors and provide a rationale for combination therapy with BQ and immune checkpoint blockade.

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