Protein arginine methyltransferase 5 (PRMT5) mediates symmetric dimethylation of arginine residues on histone and non-histone proteins. Its relevance to oncology stems from the fact that researchers have found PRMT5 to be overexpressed and dysregulated in both solid tumors and hematologic malignancies. While methylthioadenosine phosphorylase (MTAP)-deleted tumors are particularly vulnerable to pharmacologic inhibition of PRMT5, MTAP deletion is associated with poor outcome in mantle cell lymphoma (MCL). Now, findings from a study using preclinical models of MCL suggest that selective targeting of PRMT5 might be an effective treatment strategy for MCL. Shelby Sloan, PhD, a researcher at The Ohio State University (OSU) in Columbus, and colleagues published their results in Blood.
The investigators analyzed the effects of treating eight MCL cell lines with increasing concentrations of the PRMT5 inhibitor PRT-382 for nine days. They also evaluated the in vivo therapeutic activity of PRT-382 using two MCL patient-derived xenograft (PDX) mouse models. The PDX-DA model contained a homozygous mutation of TP53(R282G), whereas the PDX-AA model did not have any pathogenic mutations of TP53. When the researchers performed copy number variation analysis, they found a co-deletion of MTAP/CDKN2A (cyclin-dependent kinase inhibitor 2A) in PDX-AA, whereas PDX-DA contained loss of heterozygosity.
The team used an unbiased pharmacogenomic approach to identify the mechanisms underpinning PRMT5 inhibitor-mediated growth arrest and cell death in MCL. To do this, they first evaluated the baseline transcript expression of CDKN2A, MTAP, and PRMT5 across the eight MCL cell lines, two PDXs, five primary MCL patient samples, and resting and activated normal B cells. They then focused on the MCL cell lines with the highest PRT-382 half-maximal inhibitory concentration (IC50) and knocked down (KD) MTAP by short hairpin RNA. The investigators found that MTAP-KD resulted in a reduction in symmetric dimethylarginine that was further diminished with the addition of PRT-382.
To identify the transcriptional signatures contributing to the anti-tumor activity of PRMT5 inhibition of MCL, they investigated the transcriptomic profiles of PDX-AA cells treated in vivo for two weeks with PRT-382, ibrutinib, or vehicle control. By interrogating the transcriptional reprogramming after PRMT5 inhibition, the researchers discovered that they were able to restore regulatory activity of the cell cycle, apoptotic cell death, and activation of negative regulators of BCR-PI3K/AKT signaling. They also found that the repressive histone marker H3R8me2s was recruited to the promoter region of the B-cell receptor protein tyrosine phosphatase receptor type O (PTPRO) and that PRMT5 inhibition contributed to the loss of this methylated arginine residue and increased expression of PTPRO.
The results suggest that PRMT5 promotes MCL cell survival by regulating DNA damage repair through E2F1, a transcription factor essential for the growth and survival of MCL. Conversely, PRMT5 inhibition transcriptionally reprograms MCL cells to shut down essential growth and proliferative genes that contribute critical signals for the survival of MCL cells while simultaneously activating an inflammatory cytokine, cell death receptor, and p53 pro-apoptotic response.
“MCL is rare, but remains incurable,” said Lapo Alinari, MD, PhD, associate professor in the Division of Hematology at OSU and senior investigator of the study. He emphasized not only the medical need in this patient population but also the fact that the new findings suggest that patients with MCL with wild-type TP53 and MTAP deletion are most likely to respond to PRMT5-targeted therapy. While investigators have known that PRMT5 inhibition stabilizes and activates the p53 pathway and defines patients with a functional p53-MDM4 axis as vulnerable to PRMT5 inhibition, the new results underscore that these findings also apply to patients with MCL. While the results are preclinical, the authors call for future preclinical studies to consider the combined treatment of Bruton tyrosine kinase-targeted therapies with PRMT5 inhibitors to achieve synergistic inhibition of the B-cell receptor pathway.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Sloan SL, Brown F, Long M, et al. PRMT5 supports multiple oncogenic pathways in mantle cell lymphoma. Blood. 2023;142(10):887-902.