P1280: TARGETED INHIBITION OF DHODH IS SYNERGISTIC WITH BCL2 BLOCKADE IN LYMPHOMA WITH CONCURRENT MYC AND BCL2 REARRANGEMENT

Abstract

Background: 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 inferior survival outcomes due to relapse or refractoriness despite salvage chemotherapy with or without stem cell transplantation. 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 demonstrated that DHODH inhibitors can target MYC in some tumors. Aims: To develop and assess new therapeutics, we investigated the effects of the DHODH inhibitor brequinar in DHL lymphoma cell lines and the synthetic effects of brequinar and venetoclax. Methods: We first investigated the activity of DHODH inhibition in genetically defined double-hit DLBCL(DHL) cell lines. We then investigated whether c-MYC could be repressed by brequinar in DHL cells. Then we tried to uncover the synergistic mechanism of brequinar and venetoclax. To understand the genome-wide effects and target genes of brequinar and the combination with venetoclax, we performed an RNA-seq of SU-DHL4 cells treated with brequinar, venetoclax, or the combination of both agents versus DMSO-treated cells. At last, we confirmed the synergistic effect of DHODH inhibition and BCL2 blockade in vivo. Results: DHODH inhibition could repress DLBCL cell lines with MYC and BCL2 abnormalities. The protein level of c-MYC was upregulated 6 hours after brequinar treatment and then downregulated gradually with prolonged treatment time. The gene levels of c-MYC decreased over time. The synergistic mechanism of brequinar and venetoclax is the complementarity of different pathways. RNA-seq of SU-DHL4 cells treated with different agents further implied the possible synergistic mechanism of the two agents. Finally, in vivo study confirmed targeted inhibition of DHODH is synergistic with BCL2 blockade in lymphoma with concurrent MYC and BCL2 rearrangement Summary/Conclusion: Our study demonstrates that combined blockade of DHODH and BCL2 could synergistically inhibit DLBCL with concurrent MYC and BCL2 abnormalities through multiple pathways. Thus, it can be reasonably expected that a clinical-grade DHODH inhibitor combined with venetoclax might improve outcomes for patients with DHL or double-expression lymphoma and other cancers with high expression of MYC and BCL2 or MYC and MCL-1. Our findings provide new insights into the molecular basis of this effect and offer opportunities to design new targeted treatments for lymphoma.