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

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

  • Cell Rep Med. 2024 Mar 19;5(3):101471. doi: 10.1016/j.xcrm.2024.101471.
Mengnuo Chen 1,  Sara Mainardi 2,  Cor Lieftink 3,  Arno Velds 4,  Iris de Rink 4,  Chen Yang 5,  Hendrik J Kuiken 3,  Ben Morris 3,  Finn Edwards 2,  Fleur Jochems 2,  Olaf van Tellingen 6,  Manon Boeije 7,  Natalie Proost 7,  Robin A Jansen 2,  Shifan Qin 2,  Haojie Jin 1,  J C Koen van der Mijn 8,  Arnout Schepers 2,  Subramanian Venkatesan 2,  Wenxin Qin 5,  Roderick L Beijersbergen 9,  Liqin Wang 10,  René Bernards 11
Affiliations

Affiliations

  • 1 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.
  • 2 Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
  • 3 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.
  • 4 Genomics Core Facility, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
  • 5 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 6 Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
  • 7 Mouse Clinic for Cancer and Aging Research, Preclinical Intervention Unit, The Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands.
  • 8 Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
  • 9 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.
  • 10 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: [email protected].
  • 11 Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Electronic address: [email protected].
PMID: 38508142 DOI: 10.1016/j.xcrm.2024.101471
Abstract

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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