Exploiting PRMT5 as a Target for Combination Therapy in Mantle Cell Lymphoma Characterized by Frequent ATM and TP53 Mutations

Authors

Yuxuan Che
Yang Liu
Yixin Yao
Holly A Hill
Yijing Li
Qingsong Cai
Fangfang Yan
Preetesh Jain
Wei Wang
Lixin Rui
Michael Wang

Publication Date

2-17-2023

Journal

Blood Cancer Journal

Abstract

Constant challenges for the treatment of mantle cell lymphoma (MCL) remain to be recurrent relapses and therapy resistance, especially in patients harboring somatic mutations in the tumor suppressors ATM and TP53, which are accumulated as therapy resistance emerges and the disease progresses, consistent with our OncoPrint results that ATM and TP53 alterations were most frequent in relapsed/refractory (R/R) MCL. We demonstrated that protein arginine methyltransferase-5 (PRMT5) was upregulated in R/R MCL, which predicted a poor prognosis. PRMT5 inhibitors displayed profound antitumor effects in the mouse models of MCL with mutated ATM and/or TP53, or refractory to CD19-targeted CAR T-cell therapy. Genetic knockout of PRMT5 robustly inhibited tumor growth in vivo. Co-targeting PRMT5, and ATR or CDK4 by using their inhibitors showed synergistic antitumor effects both in vitro and in vivo. Our results have provided a rational combination therapeutic strategy targeting multiple PRMT5-coordinated tumor-promoting processes for the treatment of R/R MCL with high mutation burdens.

Keywords

Animals, Mice, Enzyme Inhibitors, Lymphoma, Mantle-Cell, Mutation, Neoplasm Recurrence, Local, Tumor Suppressor Protein p53

DOI

10.1038/s41408-023-00799-6

PMID

36797243

PMCID

PMC9935633

PubMedCentral® Posted Date

2-17-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes