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PRMT5 inhibition drives therapeutic vulnerability to combination treatment with BCL-2 inhibition in mantle cell lymphoma
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 rema...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society of Hematology
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10582835/ https://www.ncbi.nlm.nih.gov/pubmed/37327122 http://dx.doi.org/10.1182/bloodadvances.2023009906 |
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author | Brown-Burke, Fiona Hwang, Inah Sloan, Shelby Hinterschied, Claire Helmig-Mason, JoBeth Long, Mackenzie Chan, Wing Keung Prouty, Alexander Chung, Ji-Hyun Zhang, Yang Singh, Satishkumar Youssef, Youssef Bhagwat, Neha Chen, Zhengming Chen-Kiang, Selina Di Liberto, Maurizio Elemento, Olivier Sehgal, Lalit Alinari, Lapo Vaddi, Kris Scherle, Peggy Lapalombella, Rosa Paik, Jihye Baiocchi, Robert A. |
author_facet | Brown-Burke, Fiona Hwang, Inah Sloan, Shelby Hinterschied, Claire Helmig-Mason, JoBeth Long, Mackenzie Chan, Wing Keung Prouty, Alexander Chung, Ji-Hyun Zhang, Yang Singh, Satishkumar Youssef, Youssef Bhagwat, Neha Chen, Zhengming Chen-Kiang, Selina Di Liberto, Maurizio Elemento, Olivier Sehgal, Lalit Alinari, Lapo Vaddi, Kris Scherle, Peggy Lapalombella, Rosa Paik, Jihye Baiocchi, Robert A. |
author_sort | Brown-Burke, Fiona |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10582835 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | The American Society of Hematology |
record_format | MEDLINE/PubMed |
spelling | pubmed-105828352023-10-19 PRMT5 inhibition drives therapeutic vulnerability to combination treatment with BCL-2 inhibition in mantle cell lymphoma Brown-Burke, Fiona Hwang, Inah Sloan, Shelby Hinterschied, Claire Helmig-Mason, JoBeth Long, Mackenzie Chan, Wing Keung Prouty, Alexander Chung, Ji-Hyun Zhang, Yang Singh, Satishkumar Youssef, Youssef Bhagwat, Neha Chen, Zhengming Chen-Kiang, Selina Di Liberto, Maurizio Elemento, Olivier Sehgal, Lalit Alinari, Lapo Vaddi, Kris Scherle, Peggy Lapalombella, Rosa Paik, Jihye Baiocchi, Robert A. Blood Adv Lymphoid Neoplasia 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. The American Society of Hematology 2023-06-20 /pmc/articles/PMC10582835/ /pubmed/37327122 http://dx.doi.org/10.1182/bloodadvances.2023009906 Text en © 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Lymphoid Neoplasia Brown-Burke, Fiona Hwang, Inah Sloan, Shelby Hinterschied, Claire Helmig-Mason, JoBeth Long, Mackenzie Chan, Wing Keung Prouty, Alexander Chung, Ji-Hyun Zhang, Yang Singh, Satishkumar Youssef, Youssef Bhagwat, Neha Chen, Zhengming Chen-Kiang, Selina Di Liberto, Maurizio Elemento, Olivier Sehgal, Lalit Alinari, Lapo Vaddi, Kris Scherle, Peggy Lapalombella, Rosa Paik, Jihye Baiocchi, Robert A. PRMT5 inhibition drives therapeutic vulnerability to combination treatment with BCL-2 inhibition in mantle cell lymphoma |
title | PRMT5 inhibition drives therapeutic vulnerability to combination treatment with BCL-2 inhibition in mantle cell lymphoma |
title_full | PRMT5 inhibition drives therapeutic vulnerability to combination treatment with BCL-2 inhibition in mantle cell lymphoma |
title_fullStr | PRMT5 inhibition drives therapeutic vulnerability to combination treatment with BCL-2 inhibition in mantle cell lymphoma |
title_full_unstemmed | PRMT5 inhibition drives therapeutic vulnerability to combination treatment with BCL-2 inhibition in mantle cell lymphoma |
title_short | PRMT5 inhibition drives therapeutic vulnerability to combination treatment with BCL-2 inhibition in mantle cell lymphoma |
title_sort | prmt5 inhibition drives therapeutic vulnerability to combination treatment with bcl-2 inhibition in mantle cell lymphoma |
topic | Lymphoid Neoplasia |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10582835/ https://www.ncbi.nlm.nih.gov/pubmed/37327122 http://dx.doi.org/10.1182/bloodadvances.2023009906 |
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