PRMT5 supports multiple oncogenic pathways in mantle cell lymphoma
Shelby Sloan, Fiona Brown, Mackenzie Long, Christoph Weigel, Shirsha Koirala, Ji-Hyun Chung, Betsy Pray, Lynda Villagomez, Claire Hinterschied, Anuvrat Sircar, JoBeth Helmig-Mason, Alexander Prouty, Eric Brooks, Youssef Youssef, Walter Hanel, Samir Parekh, Wing Keung Chan, Zhengming Chen, Rosa Lapalombella, Lalit Sehgal, Kris Vaddi, Peggy Scherle, Selina Chen‐Kiang, Maurizio Di Liberto, Olivier Elemento, Cem Meydan, Jonathan Foox, Daniel Butler, Christopher E. Mason, Robert A. Baiocchi, Lapo Alinari
Abstract
Mantle cell lymphoma (MCL) is an incurable B-cell malignancy with an overall poor prognosis, particularly for patients that progress on targeted therapies. Novel, more durable treatment options are needed for patients with MCL. Protein arginine methyltransferase 5 (PRMT5) is overexpressed in MCL and plays an important oncogenic role in this disease via epigenetic and posttranslational modification of cell cycle regulators, DNA repair genes, components of prosurvival pathways, and RNA splicing regulators. The mechanism of targeting PRMT5 in MCL remains incompletely characterized. Here, we report on the antitumor activity of PRMT5 inhibition in MCL using integrated transcriptomics of in vitro and in vivo models of MCL. Treatment with a selective small-molecule inhibitor of PRMT5, PRT-382, led to growth arrest and cell death and provided a therapeutic benefit in xenografts derived from patients with MCL. Transcriptional reprograming upon PRMT5 inhibition led to restored regulatory activity of the cell cycle (p-RB/E2F), apoptotic cell death (p53-dependent/p53-independent), and activation of negative regulators of B-cell receptor-PI3K/AKT signaling (PHLDA3, PTPROt, and PIK3IP1). We propose pharmacologic inhibition of PRMT5 for patients with relapsed/refractory MCL and identify MTAP/CDKN2A deletion and wild-type TP53 as biomarkers that predict a favorable response. Selective targeting of PRMT5 has significant activity in preclinical models of MCL and warrants further investigation in clinical trials.