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Cancer drug-tolerant persister cells: from biological questions to clinical opportunities
Open accessAbstract
The emergence of drug resistance is the most substantial challenge to the effectiveness of anticancer therapies. Orthogonal approaches have revealed that a subset of cells, known as drug-tolerant 'persister' (DTP) cells, have a prominent role in drug resistance. Although long recognized in bacterial populations which have acquired resistance to antibiotics, the presence of DTPs in various cancer types has come to light only in the past two decades, yet several aspects of their biology remain enigmatic. Here, we delve into the biological characteristics of DTPs and explore potential strategies for tracking and targeting them. Recent findings suggest that DTPs exhibit remarkable plasticity, being capable of transitioning between different cellular states, resulting in distinct DTP phenotypes within a single tumour. However, defining the biological features of DTPs has been challenging, partly due to the complex interplay between clonal dynamics and tissue-specific factors influencing their phenotype. Moreover, the interactions between DTPs and the tumour microenvironment, including their potential to evade immune surveillance, remain to be discovered. Finally, the mechanisms underlying DTP-derived drug resistance and their correlation with clinical outcomes remain poorly understood. This Roadmap aims to provide a comprehensive overview of the field of DTPs, encompassing past achievements and current endeavours in elucidating their biology. We also discuss the prospect of future advancements in technologies in helping to unveil the features of DTPs and propose novel therapeutic strategies that could lead to their eradication.
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“DTPs share some characteristics with CSCs; however, DTPs have distinctive features such as the ability to enter transient quiescence and display phenotypic plasticity, which have crucial roles in contributing to drug resistance and tumor relapse [80].”
From Mechanisms and Strategies to Overcome Drug Resistance in Colorectal Cancer (2025) · cites this paper as [80]
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“Moreover, inhibiting autophagy could also target therapy-resistant CSCs and DTPs, both of which often have upregulated autophagy pathways [80,152].”
From Mechanisms and Strategies to Overcome Drug Resistance in Colorectal Cancer (2025) · cites this paper as [80]
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“Instead, they rely on different non-genetic mechanisms of adaptation to evade therapy-induced cell death and promote survival, including epigenetic remodeling, transcriptional or translational rewiring, altered metabolism, phenotypic plasticity, and microenvironmental interactions [80].”
From Mechanisms and Strategies to Overcome Drug Resistance in Colorectal Cancer (2025) · cites this paper as [80]
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“While biomarkers to identify DTPs are lacking, findings from various studies in different cancers suggest that DTPs can either arise from selection of a pre-existing cell population or emerge de novo during drug exposure, depending on the experimental model and treatment used [80].”
From Mechanisms and Strategies to Overcome Drug Resistance in Colorectal Cancer (2025) · cites this paper as [80]
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Mechanisms and Strategies to Overcome Drug Resistance in Colorectal Cancer
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Metadata
- Authors
- Russo, M., Chen, M., Mariella, E., Peng, H., Rehman, S. K., Sancho, E., Sogari, A., Toh, T. S., Balaban, N. Q., Batlle, E., Bernards, R., Garnett, M. J., Hangauer, M., Leucci, E., Marine, J.-C., O’Brien, C. A., Oren, Y., Patton, E. E., Robert, C., Rosenberg, S. M., Shen, S., & Bardelli, A.
- Affiliations
- IFOM (IT)
- The Netherlands Cancer Institute (NL)
- West China Hospital of Sichuan University (CN)
- University Health Network (CA)
- Institute for Research in Biomedicine (ES)
- Wellcome Sanger Institute (GB)
- Hebrew University of Jerusalem (IL)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- University of California San Diego (US)
- KU Leuven (BE)
- VIB-KU Leuven Center for Cancer Biology (BE)
- Tel Aviv University (IL)
- Edinburgh Cancer Research (GB)
- Inserm (FR)
- Baylor College of Medicine (US)
- Corresponding author
- Russo, Mariangela
- Bardelli, Alberto
- ORCID
- Russo, Mariangela
- Mariella, Elisa
- Peng, Haoning
- Sancho, Elena
- Sogari, Alberto
- Toh, Tzen S.
- Balaban, Nathalie Q.
- Batlle, Eduard
- Bernards, Rene
- Garnett, Mathew J.
- Hangauer, Matthew
- Leucci, Eleonora
- Marine, Jean-Christophe
- Oren, Yaara
- Patton, E. Elizabeth
- Robert, Caroline
- Rosenberg, Susan M.
- Shen, Shensi
- Bardelli, Alberto
- Venue
- Nature Reviews Cancer
- Published
- 2024-09-02
- Volume
- 24
- Issue
- 10
- Pages
- 694-717
- ISSN
- 1474-175X (ISSN-L)
- 1474-1768
- PMC
- PMC12622869
- OpenAlex
- W4402128677
- Cited by
- 210
- References
- 252
- Citations by year
- 2026: 127 · 2025: 77 · 2024: 6
- FWCI
- 11.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature reviews. Cancer (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, public-domain)
- Funders
- U.S. Department of Defense
- AstraZeneca
- GlaxoSmithKline
- Melanoma Research Alliance (687306, 917226)
- Wellcome Trust (220540/Z/20/A, 220540, Grant 206194, 206194)
- Astex Pharmaceuticals
- Incyte
- Revolution Medicines
- Cancer Research UK (CTRQQR-2021\\100006)
- European Commission (220540, 687306, 2021-2026, 101007937, HORIZON2020)
- Rosetrees Trust (917226, 687306)
- Agence Nationale de la Recherche
- National Natural Science Foundation of China (82172794)
- Fonds Wetenschappelijk Onderzoek (G070622N)
- KU Leuven (C1-grant)
- Krebsliga Schweiz
- KWF Kankerbestrijding
- Sichuan University
- Associazione Italiana per la Ricerca sul Cancro (MFAG 2021 - ID 26439, 28922, MFAG 2021, IG 2023, 21091, ID.21091)
- National Institutes of Health (2021-2026)
- Genentech
- Canadian Institutes of Health Research
- Medical Research Council (MC_UU_00035/13, 2021-2026)
- Agència de Gestió d'Ajuts Universitaris i de Recerca
- West China Hospital, Sichuan University
- National Institute on Aging (DP1AG072751)
- National Cancer Institute (R01CA250905)
- Coral Reef Conservation Program
- Congressionally Directed Medical Research Programs
- H2020 European Research Council (884623, 101020342)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Physical Sciences › Mathematics › Modeling and Simulation › Mathematical Biology Tumor Growth
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- drug-tolerant persister cells, chemoresistance, cellular plasticity, clonal dynamics, tumor microenvironment, immune evasion, tumor heterogeneity
- MeSH terms
- Animals, Antineoplastic Agents, Drug Tolerance, Humans, Neoplasms, Drug Resistance, Neoplasm, Tumor Microenvironment
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