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 proliferation. JNJ-64619178, a selective small-molecule inhibitor targeting PRMT5, has previously shown promising preclinical activity across a range of hematological malignancies; however, the clinical activity of JNJ-64619178 monotherapy is limited despite strong target engagement. Therefore, we sought to identify rational combination partners for JNJ-64619178 to achieve improved activity in B-cell malignancies. Using dynamic Bcl-2 homology 3 (BH3) profiling, a functional assay to evaluate the net increase in proapoptotic signaling in response to drugs, we found that JNJ-64619178 increased overall proximity to apoptotic cell death (mitochondrial apoptotic priming) and dependence on B-cell leukemia/lymphoma (BCL)-2 for survival (BCL-2 dependence), particularly in diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cell lines. In other B-cell non-Hodgkin lymphoma (B-NHL) cell lines that are primarily MCL-1 dependent and less BCL-2 dependent, JNJ-64619178 increased mitochondrial apoptotic priming without shifting 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-NHL cell lines. Interestingly, JNJ-64619178 upregulated death receptor 4 (DR4) and death receptor 5 (DR5) expression on the cell membrane of B-NHL cell lines, thereby sensitizing them, including the less BCL-2-dependent cell lines, 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 for potential clinical application in B-NHL.