Dihydroorotate dehydrogenase inhibition reveals metabolic vulnerability in chronic myeloid leukemia

The development of different generations of BCR-ABL1 tyrosine kinases inhibitors (TKIs) has led the overall survival (OS) of the chronic myeloid leukemia (CML) patients to become almost similar to that of a control population without leukemia, but the TKI therapy can be successfully discontinued only in half of those who are achieving a deep molecular response, that eans in approximately 15-20% of the entire population. In addition, although few, there are CML patients who show resistance to TKI therapy, are prone to progress to more advanced phases of the disease and die of CML related causes. Therefore, implementing an alternative approach for targeting TKI resistant leukemic cells would be of the essence in trying to solve these problems. Dihydroorotate dehydrogenase (DHODH) is a druggable enzyme in the de novo pyrimidine biosynthesis pathway that is located in the inner membrane of mitochondria. Here, we found that CML CD34+ cells and CML cell lines are vulnerable to DHODH inhibition mediated by Meds433, a new and potent DHODH inhibitor recently developed by our group. Meds433 significantly activated the apoptotic pathway and suppressed cell growth of CML cells in vitro and in vivo in a xenograft mice model. Moreover, inhibition of DHODH led to the reduction of amino acids and induction of huge metabolic stress in CML CD34+. Altogether, our study shows that targeting pyrimidine synthesis is a promising approach for targeting CML stem/progenitor cells, helping more patients to achieve good molecular response and possibly successful treatment discontinuation. Overall design: Gene expression profiling was performed on CD34+ cells from five CML patients, untreated, and after three days of treatment with Meds433 100nM, for a total of 10 matched samples.

各类BCR-ABL1酪氨酸激酶抑制剂（Tyrosine Kinase Inhibitors, TKIs）的迭代发展，使得慢性髓性白血病（Chronic Myeloid Leukemia, CML）患者的总生存期（Overall Survival, OS）已与健康对照人群基本持平；但仅半数获得深度分子学反应的患者能够成功停用TKI治疗，这一群体仅占全部患者的15%~20%左右。此外，虽占比不高，但仍有部分CML患者会出现TKI治疗耐药，病情易进展至疾病更晚期阶段，并最终死于CML相关并发症。因此，开发针对TKI耐药白血病细胞的替代治疗策略，是解决上述问题的关键所在。二氢乳清酸脱氢酶（Dihydroorotate Dehydrogenase, DHODH）是定位于线粒体内膜的可成药酶，参与嘧啶的从头生物合成途径。本研究发现，CML CD34+细胞及CML细胞系对本团队新近开发的强效新型DHODH抑制剂Meds433介导的DHODH抑制作用敏感。Meds433可显著激活细胞凋亡通路，并在体外及异种移植小鼠模型体内抑制CML细胞的增殖。此外，抑制DHODH可导致CML CD34+细胞内氨基酸水平降低，并诱发强烈的代谢应激。综上，本研究证实，靶向嘧啶合成途径是针对CML干/祖细胞的潜在治疗策略，有望帮助更多患者获得良好的分子学反应，并实现成功停药。实验整体设计：从5名未经治疗的CML患者体内分离CD34+细胞，分别在未经处理及经100nM Meds433处理3天后进行基因表达谱分析，共计获得10对匹配样本。