Cargando…

Overcoming the therapeutic limitations of EZH2 inhibitors in Burkitt’s lymphoma: a comprehensive study on the combined effects of MS1943 and Ibrutinib

Enhancer of zeste homolog 2 (EZH2) and Bruton’s tyrosine kinase (BTK) are both key factors involved in the development and progression of hematological malignancies. Clinical studies have demonstrated the potential of various EZH2 inhibitors, which target the methyltransferase activity of EZH2, for...

Descripción completa

Detalles Bibliográficos
Autores principales: Jeong, Yurim, Kim, Se Been, Yang, Chae-Eun, Yu, Min Seo, Choi, Wan-Su, Jeon, Youngwoo, Lim, Jung-Yeon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10518396/
https://www.ncbi.nlm.nih.gov/pubmed/37752998
http://dx.doi.org/10.3389/fonc.2023.1252658
_version_ 1785109504254279680
author Jeong, Yurim
Kim, Se Been
Yang, Chae-Eun
Yu, Min Seo
Choi, Wan-Su
Jeon, Youngwoo
Lim, Jung-Yeon
author_facet Jeong, Yurim
Kim, Se Been
Yang, Chae-Eun
Yu, Min Seo
Choi, Wan-Su
Jeon, Youngwoo
Lim, Jung-Yeon
author_sort Jeong, Yurim
collection PubMed
description Enhancer of zeste homolog 2 (EZH2) and Bruton’s tyrosine kinase (BTK) are both key factors involved in the development and progression of hematological malignancies. Clinical studies have demonstrated the potential of various EZH2 inhibitors, which target the methyltransferase activity of EZH2, for the treatment of lymphomas. However, despite their ability to effectively reduce the H3K27me3 levels, these inhibitors have shown limited efficacy in blocking the proliferation of lymphoma cells. To overcome this challenge, we employed a hydrophobic tagging approach utilizing MS1943, a selective EZH2 degrader. In this study, we investigated the inhibitory effects of two drugs, the FDA-approved EZH2 inhibitor Tazemetostat, currently undergoing clinical trials, and the novel drug MS1943, on Burkitt’s lymphoma. Furthermore, we assessed the potential synergistic effect of combining these drugs with the BTK inhibitor Ibrutinib. In this study, we evaluated the effects of combination therapy with MS1943 and Ibrutinib on the proliferation of three Burkitt’s lymphoma cell lines, namely RPMI1788, Ramos, and Daudi cells. Our results demonstrated that the combination of MS1943 and Ibrutinib significantly suppressed cell proliferation to a greater extent compared to the combination of Tazemetostat and Ibrutinib. Additionally, we investigated the underlying mechanisms of action and found that the combination therapy of MS1943 and Ibrutinib led to the upregulation of miR29B-mediated p53-upregulated modulator of apoptosis PUMA, BAX, cleaved PARP, and cleaved caspase-3 in Burkitt’s lymphoma cells. These findings highlight the potential of this innovative therapeutic strategy as an alternative to traditional EZH2 inhibitors, offering promising prospects for improving treatment outcomes in Burkitt’s lymphoma.
format Online
Article
Text
id pubmed-10518396
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-105183962023-09-26 Overcoming the therapeutic limitations of EZH2 inhibitors in Burkitt’s lymphoma: a comprehensive study on the combined effects of MS1943 and Ibrutinib Jeong, Yurim Kim, Se Been Yang, Chae-Eun Yu, Min Seo Choi, Wan-Su Jeon, Youngwoo Lim, Jung-Yeon Front Oncol Oncology Enhancer of zeste homolog 2 (EZH2) and Bruton’s tyrosine kinase (BTK) are both key factors involved in the development and progression of hematological malignancies. Clinical studies have demonstrated the potential of various EZH2 inhibitors, which target the methyltransferase activity of EZH2, for the treatment of lymphomas. However, despite their ability to effectively reduce the H3K27me3 levels, these inhibitors have shown limited efficacy in blocking the proliferation of lymphoma cells. To overcome this challenge, we employed a hydrophobic tagging approach utilizing MS1943, a selective EZH2 degrader. In this study, we investigated the inhibitory effects of two drugs, the FDA-approved EZH2 inhibitor Tazemetostat, currently undergoing clinical trials, and the novel drug MS1943, on Burkitt’s lymphoma. Furthermore, we assessed the potential synergistic effect of combining these drugs with the BTK inhibitor Ibrutinib. In this study, we evaluated the effects of combination therapy with MS1943 and Ibrutinib on the proliferation of three Burkitt’s lymphoma cell lines, namely RPMI1788, Ramos, and Daudi cells. Our results demonstrated that the combination of MS1943 and Ibrutinib significantly suppressed cell proliferation to a greater extent compared to the combination of Tazemetostat and Ibrutinib. Additionally, we investigated the underlying mechanisms of action and found that the combination therapy of MS1943 and Ibrutinib led to the upregulation of miR29B-mediated p53-upregulated modulator of apoptosis PUMA, BAX, cleaved PARP, and cleaved caspase-3 in Burkitt’s lymphoma cells. These findings highlight the potential of this innovative therapeutic strategy as an alternative to traditional EZH2 inhibitors, offering promising prospects for improving treatment outcomes in Burkitt’s lymphoma. Frontiers Media S.A. 2023-09-11 /pmc/articles/PMC10518396/ /pubmed/37752998 http://dx.doi.org/10.3389/fonc.2023.1252658 Text en Copyright © 2023 Jeong, Kim, Yang, Yu, Choi, Jeon and Lim https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Jeong, Yurim
Kim, Se Been
Yang, Chae-Eun
Yu, Min Seo
Choi, Wan-Su
Jeon, Youngwoo
Lim, Jung-Yeon
Overcoming the therapeutic limitations of EZH2 inhibitors in Burkitt’s lymphoma: a comprehensive study on the combined effects of MS1943 and Ibrutinib
title Overcoming the therapeutic limitations of EZH2 inhibitors in Burkitt’s lymphoma: a comprehensive study on the combined effects of MS1943 and Ibrutinib
title_full Overcoming the therapeutic limitations of EZH2 inhibitors in Burkitt’s lymphoma: a comprehensive study on the combined effects of MS1943 and Ibrutinib
title_fullStr Overcoming the therapeutic limitations of EZH2 inhibitors in Burkitt’s lymphoma: a comprehensive study on the combined effects of MS1943 and Ibrutinib
title_full_unstemmed Overcoming the therapeutic limitations of EZH2 inhibitors in Burkitt’s lymphoma: a comprehensive study on the combined effects of MS1943 and Ibrutinib
title_short Overcoming the therapeutic limitations of EZH2 inhibitors in Burkitt’s lymphoma: a comprehensive study on the combined effects of MS1943 and Ibrutinib
title_sort overcoming the therapeutic limitations of ezh2 inhibitors in burkitt’s lymphoma: a comprehensive study on the combined effects of ms1943 and ibrutinib
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10518396/
https://www.ncbi.nlm.nih.gov/pubmed/37752998
http://dx.doi.org/10.3389/fonc.2023.1252658
work_keys_str_mv AT jeongyurim overcomingthetherapeuticlimitationsofezh2inhibitorsinburkittslymphomaacomprehensivestudyonthecombinedeffectsofms1943andibrutinib
AT kimsebeen overcomingthetherapeuticlimitationsofezh2inhibitorsinburkittslymphomaacomprehensivestudyonthecombinedeffectsofms1943andibrutinib
AT yangchaeeun overcomingthetherapeuticlimitationsofezh2inhibitorsinburkittslymphomaacomprehensivestudyonthecombinedeffectsofms1943andibrutinib
AT yuminseo overcomingthetherapeuticlimitationsofezh2inhibitorsinburkittslymphomaacomprehensivestudyonthecombinedeffectsofms1943andibrutinib
AT choiwansu overcomingthetherapeuticlimitationsofezh2inhibitorsinburkittslymphomaacomprehensivestudyonthecombinedeffectsofms1943andibrutinib
AT jeonyoungwoo overcomingthetherapeuticlimitationsofezh2inhibitorsinburkittslymphomaacomprehensivestudyonthecombinedeffectsofms1943andibrutinib
AT limjungyeon overcomingthetherapeuticlimitationsofezh2inhibitorsinburkittslymphomaacomprehensivestudyonthecombinedeffectsofms1943andibrutinib