Targeting of vulnerabilities of drug-tolerant persisters identified through functional genetics delays tumor relapse
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved..
Drug-tolerant persisters (DTPs) are a rare subpopulation of cells within a tumor that can survive therapy through nongenetic adaptive mechanisms to develop relapse and repopulate the tumor following drug withdrawal. Using a cancer cell line with an engineered suicide switch to kill proliferating cells, we perform both genetic screens and compound screens to identify the inhibition of bromodomain and extraterminal domain (BET) proteins as a selective vulnerability of DTPs. BET inhibitors are especially detrimental to DTPs that have reentered the cell cycle (DTEPs) in a broad spectrum of cancer types. Mechanistically, BET inhibition induces lethal levels of ROS through the suppression of redox-regulating genes highly expressed in DTPs, including GPX2, ALDH3A1, and MGST1. In vivo BET inhibitor treatment delays tumor relapse in both melanoma and lung cancer. Our study suggests that combining standard of care therapy with BET inhibitors to eliminate residual persister cells is a promising therapeutic strategy.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:5 |
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| Enthalten in: |
Cell reports. Medicine - 5(2024), 3 vom: 19. März, Seite 101471 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Chen, Mengnuo [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 22.03.2024 Date Revised 03.04.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1016/j.xcrm.2024.101471 |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Drug-tolerant persisters (DTPs) are a rare subpopulation of cells within a tumor that can survive therapy through nongenetic adaptive mechanisms to develop relapse and repopulate the tumor following drug withdrawal. Using a cancer cell line with an engineered suicide switch to kill proliferating cells, we perform both genetic screens and compound screens to identify the inhibition of bromodomain and extraterminal domain (BET) proteins as a selective vulnerability of DTPs. BET inhibitors are especially detrimental to DTPs that have reentered the cell cycle (DTEPs) in a broad spectrum of cancer types. Mechanistically, BET inhibition induces lethal levels of ROS through the suppression of redox-regulating genes highly expressed in DTPs, including GPX2, ALDH3A1, and MGST1. In vivo BET inhibitor treatment delays tumor relapse in both melanoma and lung cancer. Our study suggests that combining standard of care therapy with BET inhibitors to eliminate residual persister cells is a promising therapeutic strategy | ||
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| 700 | 1 | |a Lieftink, Cor |e verfasserin |4 aut | |
| 700 | 1 | |a Velds, Arno |e verfasserin |4 aut | |
| 700 | 1 | |a de Rink, Iris |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Chen |e verfasserin |4 aut | |
| 700 | 1 | |a Kuiken, Hendrik J |e verfasserin |4 aut | |
| 700 | 1 | |a Morris, Ben |e verfasserin |4 aut | |
| 700 | 1 | |a Edwards, Finn |e verfasserin |4 aut | |
| 700 | 1 | |a Jochems, Fleur |e verfasserin |4 aut | |
| 700 | 1 | |a van Tellingen, Olaf |e verfasserin |4 aut | |
| 700 | 1 | |a Boeije, Manon |e verfasserin |4 aut | |
| 700 | 1 | |a Proost, Natalie |e verfasserin |4 aut | |
| 700 | 1 | |a Jansen, Robin A |e verfasserin |4 aut | |
| 700 | 1 | |a Qin, Shifan |e verfasserin |4 aut | |
| 700 | 1 | |a Jin, Haojie |e verfasserin |4 aut | |
| 700 | 1 | |a Koen van der Mijn, J C |e verfasserin |4 aut | |
| 700 | 1 | |a Schepers, Arnout |e verfasserin |4 aut | |
| 700 | 1 | |a Venkatesan, Subramanian |e verfasserin |4 aut | |
| 700 | 1 | |a Qin, Wenxin |e verfasserin |4 aut | |
| 700 | 1 | |a Beijersbergen, Roderick L |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Liqin |e verfasserin |4 aut | |
| 700 | 1 | |a Bernards, René |e verfasserin |4 aut | |
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