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

Fiona Brown-Burke, Inah Hwang, Shelby Sloan, Claire Hinterschied, Jo Beth Helmig-Mason, Mackenzie Long, Wing Keung Chan, Alexander Prouty, Ji Hyun Chung, Yang Zhang, Satishkumar Singh, Youssef Youssef, Neha Bhagwat, Zhengming Chen, Selina Chen-Kiang, Maurizio Di Liberto, Olivier Elemento, Lalit Sehgal, Lapo Alinari, Kris VaddiPeggy Scherle, Rosa Lapalombella, Jihye Paik, Robert A. Baiocchi

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Mantle cell lymphoma (MCL) is an incurable B-cell malignancy that comprises 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 5 years, and for most patients who progress on targeted agents, survival remains at a dismal 3 to 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 antitumor activity in MCL cell lines and preclinical murine models. PRMT5 inhibition reduced the activity of prosurvival AKT signaling, which led to the nuclear translocation of FOXO1 and modulation of its transcriptional activity. Chromatin immunoprecipitation and sequencing identified multiple proapoptotic 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 treatments were performed in 9 MCL lines. Loewe synergy scores showed significant levels of synergy in most MCL lines tested. Preclinical, in vivo evaluation of this strategy in multiple MCL models showed therapeutic synergy with combination venetoclax/PRT382 treatment with an increased survival advantage in 2 patient-derived xenograft models (P ≤ .0001, P ≤ .0001). Our results provide mechanistic rationale for the combination of PRMT5 inhibition and venetoclax to treat patients with MCL.

Original languageEnglish
Pages (from-to)6211-6224
Number of pages14
JournalBlood Advances
Volume7
Issue number20
DOIs
StatePublished - 24 Oct 2023

Bibliographical note

Publisher Copyright:
© 2023 by The American Society of Hematology

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