Department of Medicinal Chemistry, University of Michigan College of Pharmacy, Rogel Cancer Center, Ann Arbor, MI 48109, USA.
Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Pharmacol Ther. 2019 Mar;195:111-131. doi: 10.1016/j.pharmthera.2018.10.012. Epub 2018 Oct 19.
Identified as a hallmark of cancer, metabolic reprogramming allows cancer cells to rapidly proliferate, resist chemotherapies, invade, metastasize, and survive a nutrient-deprived microenvironment. Rapidly growing cells depend on sufficient concentrations of nucleotides to sustain proliferation. One enzyme essential for the de novo biosynthesis of pyrimidine-based nucleotides is dihydroorotate dehydrogenase (DHODH), a known therapeutic target for multiple diseases. Brequinar, leflunomide, and teriflunomide, all of which are potent DHODH inhibitors, have been clinically evaluated but failed to receive FDA approval for the treatment of cancer. Inhibition of DHODH depletes intracellular pyrimidine nucleotide pools and results in cell cycle arrest in S-phase, sensitization to current chemotherapies, and differentiation in neural crest cells and acute myeloid leukemia (AML). Furthermore, DHODH is a synthetic lethal susceptibility in several oncogenic backgrounds. Therefore, DHODH-targeted therapy has potential value as part of a combination therapy for the treatment of cancer. In this review, we focus on the de novo pyrimidine biosynthesis pathway as a target for cancer therapy, and in particular, DHODH. In the first part, we provide a comprehensive overview of this pathway and its regulation in cancer. We further describe the relevance of DHODH as a target for cancer therapy using bioinformatic analyses. We then explore the preclinical and clinical results of pharmacological strategies to target the de novo pyrimidine biosynthesis pathway, with an emphasis on DHODH. Finally, we discuss potential strategies to harness DHODH as a target for the treatment of cancer.
代谢重编程被认为是癌症的一个标志，它使癌细胞能够快速增殖、抵抗化疗、侵袭、转移和在营养缺乏的微环境中存活。快速生长的细胞依赖于足够浓度的核苷酸来维持增殖。二氢乳清酸脱氢酶（DHODH）是嘧啶核苷酸从头生物合成所必需的一种酶，是多种疾病的已知治疗靶点。布喹那、来氟米特和特立氟胺都是强效的 DHODH 抑制剂，已在临床上进行了评估，但未能获得 FDA 批准用于癌症治疗。DHODH 的抑制会耗尽细胞内嘧啶核苷酸池，并导致细胞周期在 S 期停滞，对当前的化疗药物敏感，并使神经嵴细胞和急性髓细胞白血病（AML）分化。此外，DHODH 是几种致癌背景下的合成致死易感性。因此，DHODH 靶向治疗具有作为癌症联合治疗一部分的潜在价值。在这篇综述中，我们重点关注从头嘧啶生物合成途径作为癌症治疗的靶点，特别是 DHODH。在第一部分，我们全面概述了该途径及其在癌症中的调控。我们进一步描述了 DHODH 作为癌症治疗靶点的相关性，使用生物信息学分析。然后，我们探讨了针对从头嘧啶生物合成途径的药理学策略的临床前和临床结果，重点是 DHODH。最后，我们讨论了利用 DHODH 作为癌症治疗靶点的潜在策略。
