PDF(Pubmed)
Abstract：
High-grade B-cell lymphoma (HGBCL), the subtype of non-Hodgkin lymphoma, to be relapsed or refractory in patients after initial therapy or salvage chemotherapy. Dual dysregulation of MYC and BCL2 is one of the important pathogenic mechanisms. Thus, combined targeting of MYC and BCL2 appears to be a promising strategy. Dihydroorotate dehydrogenase (DHODH) is the fourth rate-limiting enzyme for the de novo biosynthesis of pyrimidine. It has been shown to be a potential therapeutic target for multiple diseases. In this study, the DHODH inhibitor brequinar exhibited growth inhibition, cell cycle blockade, and apoptosis promotion in HGBCL cell lines with MYC and BCL2 rearrangements. The combination of brequinar and BCL2 inhibitors venetoclax had a synergistic inhibitory effect on the survival of DHL cells through different pathways. Venetoclax could upregulate MCL-1 and MYC expression, which has been reported as a resistance mechanism of BCL2 inhibitors. Brequinar downregulated MCL-1 and MYC, which could potentially overcome drug resistance to venetoclax in HGBCL cells. Furthermore, brequinar could downregulate a broad range of genes, including ribosome biosynthesis genes, which might contribute to its anti-tumor effects. In vivo studies demonstrated synergetic tumor growth inhibition in xenograft models with brequinar and venetoclax combination treatment. These results provide preliminary evidence for the rational combination of DHODH and BCL2 blockade in HGBCL with abnormal MYC and BCL2.
摘要：
高级别B细胞淋巴瘤（HGBCL），非霍奇金淋巴瘤的亚型,患者在初始治疗或挽救性化疗后复发或难治性。MYC和BCL2的双重失调是其重要致病机制之一。因此，MYC和BCL2的联合靶向似乎是一个有前途的策略。二氢乳清酸脱氢酶(DHODH)是嘧啶从头生物合成的第四限速酶。它已被证明是多种疾病的潜在治疗靶标。在这项研究中,DHODH抑制剂brequinar表现出生长抑制，细胞周期阻断，MYC和BCL2重排促进HGBCL细胞系的凋亡。brequinar和BCL2抑制剂venetoclax通过不同途径对DHL细胞的存活具有协同抑制作用。维奈托克可以上调MCL-1和MYC的表达，已被报道为BCL2抑制剂的耐药机制。Brequinar下调MCL-1和MYC，这可能会克服HGBCL细胞对维奈托克的耐药性。此外，布雷那可以下调广泛的基因，包括核糖体生物合成基因，这可能有助于其抗肿瘤作用。体内研究表明，在布基那和维奈托克联合治疗的异种移植模型中，肿瘤生长具有协同抑制作用。这些结果为在MYC和BCL2异常的HGBCL中合理组合DHODH和BCL2阻断提供了初步证据。
