Exploiting Prmt5, A Metabolic And Epigenetic Regulator, As A Novel Therapeutic Target In Mantle Cell Lymphoma

Distinct genetic and epigenetic alterations as well as metabolic reprogramming are among the hallmarks of mantle cell lymphoma (MCL), an incurable cancer. Deletion of MTAP, encoding 5-Methylthioadenosine phosphorylase (MTAP), results in the accumulation of metabolite methylthioadenosine (MTA), a selective inhibitor of the catalytic activity of protein arginine methyltransferase 5 (PRMT5). MTAP loss therefore presents a passenger vulnerability to PRMT5 inhibition. PRMT5 is a type II protein arginine methyltransferase that is involved in cellular processes via the regulation of the active status of transcription by symmetric dimethylation of arginine in histones, and the post-translational modification by symmetric dimethylation of arginine in nuclear and cytoplasmic oncoproteins and tumor suppressors. We recently reported that CDKN2A and MTAP were commonly co-deleted in ibrutinib-resistant MCL tumors. Consistently, PRMT5 was found to be selectively over expressed in ibrutinib-resistant MCL cells. Metabolomics analysis revealed that both the substrate (S-Adenosylmethionine) and the product (S-adenosylhomocysteine) of the PRMT5 enzyme are elevated in ibrutinib-resistant MCL, suggesting an increase in PRMT5 enzymatic activity. Importantly, our clinical data analysis indicates that the expression levels of PRMT5 in MCL patients are inversely correlated with patient responses to ibrutinib treatment. Moreover, pharmacological blockade with the PRMT5 specific inhibitor, GSK3226595, significantly inhibited tumor growth in ibrutinib-resistant MCL PDX models, demonstrating that PRMT5 is an actionable target in MCL. Mechanistically, PRMTs play an important role in mRNA splicing, among which MDM4 mRNA was identified as one of the key mRNAs that senses defects in the spliceosomal machinery during PRMT5 deficiency. Alternative splicing of MDM4 mRNA reduces the expression of Mdm2 and Mdm4 E3 ligases, leading to the upregulation of p53. Selective overexpression of PRMT5 in MCL may drive repressive epigenetic marks on chromatin to silence regulatory and tumor suppressor genes. Inhibition of PRMT5 reverses PRMT5-catalyzed epigenetic marks, restores regulatory pathways and induces cell death in ibrutinib-resistant primary MCL. Taken together, sustained PRMT5 expression and activity presents a vulnerability in ibrutinib-resistant MCL where MTAP is frequently deleted. As metabolic reprogramming towards OXPHOS is one of the hallmarks of ibrutinib-resistant MCL, combinatory inhibition of OXPHOS and PRMT5 may represent a rational therapeutic strategy that ultimately eradicates MCL. Citation Format: Yixin Yao, Lingzhi Li, Liang Zhang, Shaojun Zhang, Hui Guo, Hui Zhang, Maria Badillo, Zhihong Chen, Kimberly Hartig, Preetesh Jain, Krystle Nomie, Linghua Wang, Michael Wang. Exploiting PRMT5, a metabolic and epigenetic regulator, as a novel therapeutic target in mantle cell lymphoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 652.