Inhibition of PRMT5 sensitizes B-cell non-Hodgkin lymphoma cells to both intrinsic and extrinsic apoptotic cell death

Protein arginine methyltransferase 5 (PRMT5), a type II arginine methyltransferase, is overexpressed in several aggressive B cell malignancies and facilitates cancer cell growth. JNJ-64619178, a selective small molecule inhibitor targeting PRMT5, has previously shown promising pre-clinical activity across a range of hematologic malignancies; however, the clinical activity of JNJ-64619178 monotherapy is limited despite strong target engagement. Thus, we sought to identify rational combination partners for JNJ-64619178 to achieve improved activity in B cell malignancies. Using dynamic BH3 profiling, a functional assay to evaluate the net increase in pro-apoptotic signaling in response to drugs, we found that JNJ-64619178 increased mitochondrial apoptotic priming and BCL-2 dependence particularly in diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma cell lines (MCL).In other B-cell non-Hodgkin lymphoma (NHL) cell lines that are primarily MCL-1 dependent and less BCL-2 dependent, JNJ-64619178 increased mitochondrial apoptotic priming without switching anti-apoptotic dependence from MCL-1 to BCL-2. Co-targeting PRMT5 and BCL-2 synergistically induced apoptosis in DLBCL and MCL cell lines that displayed at least partial BCL-2 dependence at baseline but not in less BCL-2-dependent B-cell NHL cell lines. Interestingly, we found that JNJ-64619178 upregulated DR4 and DR5 expression on the cell membrane of B-cell NHL cells, thereby sensitizing them to recombinant TRAIL-induced extrinsic apoptotic cell death. These findings highlight a role of PRMT5 in regulating both intrinsic and extrinsic apoptosis and suggest potential combination partners with PRMT5 inhibitors to explore for potential clinical application in B-cell NHL.