Prmt5 inhibition restarts a pro‐apoptotic program and creates vulnerability to combination treatment with bcl‐2 inhibitor venetoclax in mantle cell lymphoma

Mantle cell lymphoma (MCL) is an incurable B cell malignancy, comprising 5% of non-Hodgkin lymphomas diagnosed annually. MCL is associated with a poor prognosis due to emergence of resistance to immuno-chemotherapy and targeted agents. The average overall survival of patients with MCL is 4-6 years and for the majority of patients who progress on targeted agents, survival remains at a dismal 3-8 months. There is a major unmet need to identify new therapeutic approaches that are well tolerated to improve treatment outcomes and quality of life. The type II protein arginine methyltransferase enzyme, PRMT5 is overexpressed and promotes growth and survival of MCL. Inhibition of PRMT5 with a novel, SAM-competitive class of inhibitors drives anti-tumor activity in MCL cell lines and patient derived xenograft models derived from patients with relapse or refractory disease. Selective inhibition of PRMT5 in these models and MCL cell lines leads to disruption of constitutive PI3K/AKT signaling, dephosphorylation and nuclear translocation of FOXO1, and enhanced recruitment of this tumor suppressor protein to target genes. By performing chromatin immunoprecipitation-seq analysis, we identified over 800 newly emerged FOXO1-bound genomic loci, among which pro-apoptotic BH3 family members including multiple pro-apoptotic BCL2 family proteins. BAX was identified as the most common direct target of FOXO1-transriptional activity which led us to hypothesize that PRMT5 inhibition could potentially drive a therapeutic vulnerability to the BCL-2 inhibitor venetoclax. Single agent and combination treatment with venetoclax and PRT382 was performed in nine MCL lines and IC50 and synergy scores showed significant levels of synergy in the majority of MCL lines tested. CCMCL1, a BCL-2 negative MCL line, and Maver1, which is highly resistant to PRMT5i, were the only cell lines to not show synergy. The cell line with the highest levels of synergy, Z-138, expressed high levels of BCL-2 and is ibrutinib resistant. Overall, there was a strong positive correlation between BCL-2 expression and synergy score (r = -0.8956, p = 0.0064). In vivo evaluation in two preclinical MCL models showed therapeutic synergy with combination venetoclax/PRT382 treatment. Mice were treated with sub-therapeutic doses of venetoclax and/or PRT382 and disease burden was assessed weekly via flow cytometry. Combination treatment with well-tolerated doses of venetoclax and PRMT5 inhibitors in the MCL in vivo models showed synergistic anti-tumor activity. Both PDX models showed an extension of life with combination treatment (P < 0.001) and delayed disease progression (P < 0.05). This preclinical data provides mechanistic rationale while demonstrating therapeutic synergy in this preclinical study and justifies further consideration of this combination strategy targeting PRMT5 and BCL2 in MCL in the clinical setting. EA – previously submitted to EHA 2021. The research was funded by: The College of Medicine at The Ohio State University, USA; The NIH, USA; Prelude Therapeutics, USA; Keywords: Genomics, Epigenomics, and Other -Omics, Molecular Targeted Therapies, Combination Therapies Conflicts of interests pertinent to the abstract Y. Zhang Employment or leadership position: Prelude Therapeutics P. Scherle Employment or leadership position: Prelude Therapeutics K. Vaddi Employment or leadership position: Prelude Therapeutics R. A. Baiocchi Consultant or advisory role: Prelude Therapeutics Research funding: Prelude Therapeutics