PDF(Pubmed)
Abstract：
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 activity in phase 1 and 2 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.
摘要：
嘧啶核苷酸的生物合成是癌细胞的药物代谢依赖性，和以嘧啶代谢为目标的化疗药物是许多癌症治疗的支柱。二氢乳清酸脱氢酶（DHODH）是嘧啶从头生物合成途径中的必需酶，可被临床批准的抑制剂靶向。然而,尽管具有强大的临床前抗癌功效，DHODH抑制剂在1期和2期临床试验中显示出有限的单药活性。因此,新的联合治疗策略对于实现这些药物的潜力是必要的.为了寻找DHODH抑制引起的治疗脆弱性，我们检测了用强效和选择性DHODH抑制剂brequinar(BQ)处理的癌细胞的基因表达变化.这表明BQ处理引起抗原呈递途径基因和细胞表面MHCI类表达的上调。机制研究表明，这种作用是（1）严格依赖于嘧啶核苷酸的消耗，(2)独立于经典抗原呈递途径的转录调控因子,和（3）通过正转录延伸因子B（P-TEFb）的RNA聚合酶II延伸控制。此外，BQ在免疫活性B16F10黑色素瘤模型中显示出令人印象深刻的单药疗效，与任一单独疗法相比,BQ和双重免疫检查点阻断(抗CTLA-4加抗PD-1)的组合治疗显著延长小鼠存活。我们的结果对DHODH抑制剂的临床开发具有重要意义，并为BQ和免疫检查点阻断的联合治疗提供了理论基础。
