Targeting of vulnerabilities of drug-tolerant persisters identified through functional genetics delays tumor relapse.

Autor:	Chen M; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Mainardi S; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Lieftink C; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands; NKI Robotics and Screening Center, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Velds A; Genomics Core Facility, The Netherlands Cancer Institute, Amsterdam, the Netherlands., de Rink I; Genomics Core Facility, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Yang C; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Kuiken HJ; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands; NKI Robotics and Screening Center, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Morris B; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands; NKI Robotics and Screening Center, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Edwards F; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Jochems F; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands., van Tellingen O; Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Boeije M; Mouse Clinic for Cancer and Aging Research, Preclinical Intervention Unit, The Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands., Proost N; Mouse Clinic for Cancer and Aging Research, Preclinical Intervention Unit, The Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands., Jansen RA; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Qin S; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Jin H; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Koen van der Mijn JC; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Schepers A; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Venkatesan S; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Qin W; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Beijersbergen RL; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands; NKI Robotics and Screening Center, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Genomics Core Facility, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Wang L; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands; State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China. Electronic address: l.wang@nki.nl., Bernards R; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Electronic address: r.bernards@nki.nl.
Jazyk:	angličtina
Zdroj:	Cell reports. Medicine [Cell Rep Med] 2024 Mar 19; Vol. 5 (3), pp. 101471.
DOI:	10.1016/j.xcrm.2024.101471
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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