PRMT5 inhibition drives therapeutic vulnerability to combination treatment with BCL-2 inhibition in mantle cell lymphoma

Abstract

Mantle cell lymphoma (MCL) is an incurable B cell malignancy, comprising up to 6% of non-Hodgkin lymphomas diagnosed annually and is associated with a poor prognosis. The average overall survival of patients with MCL is five years and for the majority of patients who progress on targeted agents, survival remains at a dismal 3-8 months. There is a major unmet need to identify new therapeutic approaches that are well tolerated to improve treatment outcomes and quality of life. The protein arginine methyltransferase 5 (PRMT5) enzyme is overexpressed in MCL and promotes growth and survival. Inhibition of PRMT5 drives anti-tumor activity in MCL cell lines and preclinical murine models. PRMT5 inhibition reduced the activity of pro-survival AKT signaling which led to nuclear translocation of FOXO1 and modulation of its transcriptional activity. Chromatin immunoprecipitation and sequencing (ChIP-seq) identified multiple pro-apoptotic BCL-2 family members as FOXO1-bound genomic loci. We identified BAX as a direct transcriptional target of FOXO1 and demonstrated its critical role in the synergy observed between the selective PRMT5 inhibitor, PRT382 and the BCL-2 inhibitor, venetoclax. Single agent and combination treatment was performed in nine MCL lines. Loewe synergy scores showed significant levels of synergy in the majority of MCL lines tested. Preclinical, in vivo evaluation of this strategy in multiple MCL models showed therapeutic synergy with combination venetoclax/PRT382 treatment with increased survival advantage in two PDX models (p=<0.0001, p=<0.0001). Our results provide mechanistic rationale for combination PRMT5 inhibition and venetoclax to treat patients with MCL.