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

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.