Unleashing the Power of NR4A1 Degradation as a Novel Strategy for Cancer Immunotherapy

An effective cancer therapy requires both killing cancer cells and targeting tumor-promoting pathways or cell populations within the tumor microenvironment (TME). We purposely search for molecules that are critical for multiple tumor-promoting cell types and identified nuclear receptor subfamily 4 g...

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Autores principales: Wang, Lei, Xiao, Yufeng, Luo, Yuewan, Master, Rohan P, Mo, Jiao, Kim, Myung-Chul, Liu, Yi, Patel, Urvi M, Li, Xiangming, Shaffer, Donald, Guertin, Kevin R, Moser, Emily, Smalley, Keiran S., Zhou, Daohong, Zheng, Guangrong, Zhang, Weizhou
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10441411/
https://www.ncbi.nlm.nih.gov/pubmed/37609171
http://dx.doi.org/10.1101/2023.08.09.552650
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author Wang, Lei
Xiao, Yufeng
Luo, Yuewan
Master, Rohan P
Mo, Jiao
Kim, Myung-Chul
Liu, Yi
Patel, Urvi M
Li, Xiangming
Shaffer, Donald
Guertin, Kevin R
Moser, Emily
Smalley, Keiran S.
Zhou, Daohong
Zheng, Guangrong
Zhang, Weizhou
author_facet Wang, Lei
Xiao, Yufeng
Luo, Yuewan
Master, Rohan P
Mo, Jiao
Kim, Myung-Chul
Liu, Yi
Patel, Urvi M
Li, Xiangming
Shaffer, Donald
Guertin, Kevin R
Moser, Emily
Smalley, Keiran S.
Zhou, Daohong
Zheng, Guangrong
Zhang, Weizhou
author_sort Wang, Lei
collection PubMed
description An effective cancer therapy requires both killing cancer cells and targeting tumor-promoting pathways or cell populations within the tumor microenvironment (TME). We purposely search for molecules that are critical for multiple tumor-promoting cell types and identified nuclear receptor subfamily 4 group A member 1 (NR4A1) as one such molecule. NR4A1 has been shown to promote the aggressiveness of cancer cells and maintain the immune suppressive TME. Using genetic and pharmacological approaches, we establish NR4A1 as a valid therapeutic target for cancer therapy. Importantly, we have developed the first-of-its kind proteolysis-targeting chimera (PROTAC, named NR-V04) against NR4A1. NR-V04 effectively degrades NR4A1 within hours of treatment in vitro and sustains for at least 4 days in vivo, exhibiting long-lasting NR4A1-degradation in tumors and an excellent safety profile. NR-V04 leads to robust tumor inhibition and sometimes eradication of established melanoma tumors. At the mechanistic level, we have identified an unexpected novel mechanism via significant induction of tumor-infiltrating (TI) B cells as well as an inhibition of monocytic myeloid derived suppressor cells (m-MDSC), two clinically relevant immune cell populations in human melanomas. Overall, NR-V04-mediated NR4A1 degradation holds promise for enhancing anti-cancer immune responses and offers a new avenue for treating various types of cancer.
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spelling pubmed-104414112023-08-22 Unleashing the Power of NR4A1 Degradation as a Novel Strategy for Cancer Immunotherapy Wang, Lei Xiao, Yufeng Luo, Yuewan Master, Rohan P Mo, Jiao Kim, Myung-Chul Liu, Yi Patel, Urvi M Li, Xiangming Shaffer, Donald Guertin, Kevin R Moser, Emily Smalley, Keiran S. Zhou, Daohong Zheng, Guangrong Zhang, Weizhou bioRxiv Article An effective cancer therapy requires both killing cancer cells and targeting tumor-promoting pathways or cell populations within the tumor microenvironment (TME). We purposely search for molecules that are critical for multiple tumor-promoting cell types and identified nuclear receptor subfamily 4 group A member 1 (NR4A1) as one such molecule. NR4A1 has been shown to promote the aggressiveness of cancer cells and maintain the immune suppressive TME. Using genetic and pharmacological approaches, we establish NR4A1 as a valid therapeutic target for cancer therapy. Importantly, we have developed the first-of-its kind proteolysis-targeting chimera (PROTAC, named NR-V04) against NR4A1. NR-V04 effectively degrades NR4A1 within hours of treatment in vitro and sustains for at least 4 days in vivo, exhibiting long-lasting NR4A1-degradation in tumors and an excellent safety profile. NR-V04 leads to robust tumor inhibition and sometimes eradication of established melanoma tumors. At the mechanistic level, we have identified an unexpected novel mechanism via significant induction of tumor-infiltrating (TI) B cells as well as an inhibition of monocytic myeloid derived suppressor cells (m-MDSC), two clinically relevant immune cell populations in human melanomas. Overall, NR-V04-mediated NR4A1 degradation holds promise for enhancing anti-cancer immune responses and offers a new avenue for treating various types of cancer. Cold Spring Harbor Laboratory 2023-08-13 /pmc/articles/PMC10441411/ /pubmed/37609171 http://dx.doi.org/10.1101/2023.08.09.552650 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Wang, Lei
Xiao, Yufeng
Luo, Yuewan
Master, Rohan P
Mo, Jiao
Kim, Myung-Chul
Liu, Yi
Patel, Urvi M
Li, Xiangming
Shaffer, Donald
Guertin, Kevin R
Moser, Emily
Smalley, Keiran S.
Zhou, Daohong
Zheng, Guangrong
Zhang, Weizhou
Unleashing the Power of NR4A1 Degradation as a Novel Strategy for Cancer Immunotherapy
title Unleashing the Power of NR4A1 Degradation as a Novel Strategy for Cancer Immunotherapy
title_full Unleashing the Power of NR4A1 Degradation as a Novel Strategy for Cancer Immunotherapy
title_fullStr Unleashing the Power of NR4A1 Degradation as a Novel Strategy for Cancer Immunotherapy
title_full_unstemmed Unleashing the Power of NR4A1 Degradation as a Novel Strategy for Cancer Immunotherapy
title_short Unleashing the Power of NR4A1 Degradation as a Novel Strategy for Cancer Immunotherapy
title_sort unleashing the power of nr4a1 degradation as a novel strategy for cancer immunotherapy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10441411/
https://www.ncbi.nlm.nih.gov/pubmed/37609171
http://dx.doi.org/10.1101/2023.08.09.552650
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