Targeted inhibition of DHODH is synergistic with BCL2 blockade in lymphoma with concurrent MYC and BCL2 rearrangement

Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma, can be cured in approximately two-thirds of patients after initial therapy. The remaining one-third of patients have very poor survival outcomes due to relapse or refractoriness despite salvage chemotherapy with or without stem cell transplantation, and the dual dysregulation of MYC and BCL2 is one of the most important pathogenic mechanisms. Thus, new therapies are needed to improve the prognosis of patients, and 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 and has been shown to be a potential therapeutic target for multiple diseases. Recent data have shown that DHODH inhibitors can target MYC in some tumors. In this study, the DHODH inhibitor brequinar exhibited effects of growth inhibition, cell cycle blockade, and apoptosis promotion in DLBCL cell lines with MYC and BCL2 rearrangements (double-hit lymphoma, DHL), accompanied by decreased MYC levels and rescue by uridine. The combination of brequinar and BCL2 inhibitors (venetoclax) had a synergistic inhibitory effect on the survival of DHL cells through different pathways. Intriguingly, venetoclax could upregulate MCL-1, which has been reported as the resistance mechanism of BCL2 inhibitors, as well as MYC expression. Brequinar showed negative effects on MCL-1 and MYC, which could potentially overcome drug resistance to venetoclax in DLBCL cells. Furthermore, brequinar could downregulate a broad range of genes, including ribosome biosynthesis genes, which might contribute to its antitumor effects. These results provide preliminary evidence for the rational combination of DHODH and BCL2 blockade in DLBCL with abnormal MYC and BCL2.