Abstract
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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Acknowledgements
The authors (post-doctoral scientists and principal investigators) are listed in the alphabetical order. The research leading to these results has received funding from: European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (TARGET, grant agreement no. 101020342) (A.B.); AIRC under 5 per Mille 2018 — ID 21091 programme — prinicipal investigator Bardelli Alberto (A.B.); IMI contract no. 101007937 PERSIST-SEQ (A.B., E.B., R.B. and M.J.G.); AIRC under IG 2023 — ID 28922 project — prinicipal investigator Bardelli Alberto (A.B.); AIRC under MFAG 2021-ID 26439 project (M.R.); Generalitat de Calatonia AGAUR 2021 SGR 001278 (E.B.); ERC advanced grant 884623 (E.B.); AECC — GEACC19006BAT (E.B.); Medical Research Council (MC_UU_00035/13) and Melanoma Research Alliance and Rosetrees Trust (MRA awards 687306 and 917226) (E.E.P.); Cancer Research UK Scotland Centre (CTRQQR-2021/100006) (E.E.P.); National Natural Science Foundation of China 82172794, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Y2022JC002 (S.S.); AIRC ‘Professoressa Fiamma Nicolodi’ Postdoc Fellowship for Italy, project 28518 (A.S.); Wellcome Trust grant 206194 (M.J.G.); Wellcome Sanger Institute Quinquennial Review 2021–2026, Wellcome Core 220540/Z/20/A (T.S.T.); FWO G0B3620N KU Leuven (E.L.); KU Leuven C1 grant 3M190246 (E.L.); DOD CDMRP Melanoma Research Program awards ME220037 and ME230211, Curebound Foundation Discovery Grant (M.H.); Canadian Institutes of Health Research (PJT 175232), the Canadian Cancer Society (707484) and Canada Research Chair in Translational Colorectal Cancer Research (CRCP) (C.A.O.); Canadian Institutes of Health Research (ED0 190701) (S.K.R.); US NIH R01-CA250905 (S.M.R.) and NIH Director’s Pioneer Award DP1-AG072751 (S.M.R.); Worldwide Cancer Research (22-0052) (J.-C.M.); the VIB Grand Challenges Program (POINTILLISM 2.0) (J.-C.M.); FWO (G0C530N and G070622N) (J.-C.M.); Stichting tegen kanker (FAF-F/2018/1265) (J.-C.M.); the Belgian Excellence of Science (EOS) and Interuniversity BOF (iBOF) programmes (J.-C.M.).
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M.R., E.M., S.K.R., E.S., A.S., T.S.T., M.C., H.P. and A.B. researched data for the article. M.R., N.Q.B., E.B., R.B., M.J.G., M.H., E.L., J.-C.M., C.A.O., Y.O., E.E.P., C.R., S.M.R., S.S. and A.B. contributed substantially to discussion of the content. All authors wrote the article and reviewed and/or edited the manuscript before submission.
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A.B. reports receipt of grants/research supports from Neophore, AstraZeneca and Boehringer Ingelheim and honoraria/consultation fees from Guardant Health and Inivata. A.B. is a stock shareholder of Neophore and Kither Biotech. A.B. is an advisory boards member for Inivata, Neophore and Roche/Genentech. E.B. provides consultancy services to Roche, and his laboratory has entered into sponsored research agreements and received funding from Merus NL, Incyte and Revolution Medicines. S.S. reports personal fees from Agence nationale de la recherche (France), Krebsliga Schweiz (Switzerland), KWF Kankerbestrijding (The Netherlands) and Shenzhen Medical Academy of Research and Translation (China). M.J.G. has received research grants from AstraZeneca, GlaxoSmithKline and Astex Pharmaceuticals and is a consultant for and holds equity in Mosaic Therapeutics. M.H. is a cofounder and consultant for, and has received research grant funding from, Ferro Therapeutics (BridgeBio). M.R., M.C., E.M., H.P., S.K.R., E.S., A.S., T.S.T., N.Q.B., R.B., E.L., J.-C.M., C.A.O., Y.O., E.E.P., C.R. and S.M.R. declare no competing interests.
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Related links
European PERSIST-SEQ consortium: https://persist-seq.org/
Glossary
- Artificial-intelligence-designed enhancers
-
Starting from a collection of random sequences, deep learning models are used to design synthetic sequences that act as cell-type-specific enhancers to better understand the regulatory logic of enhancers and, ultimately, how they can be altered to manipulate cell states.
- Autophagic flux
-
The process measuring autophagosome formation, fusion with lysosomes and degradation of autophagic cargo.
- Glycocalyx
-
A carbohydrate layer on cell surfaces, aiding cellular protection and communication.
- Homology-directed repair
-
An error-free mechanism by which cells repair DNA double-stranded breaks using a sister DNA molecule as a template.
- Mismatch repair
-
A DNA repair pathway that allows cells to detect and correct the insertion, deletion and misincorporation of nucleotides that can occur in the newly synthesized strand during DNA replication.
- Oxidative phosphorylation
-
(OXPHOS). The process of ATP production by the mitochondrial electron transport chain.
- Quorum sensing
-
A process of cell–cell communication that allows bacteria to share information about cell density and adjust gene expression accordingly.
- Retrotransposons
-
Repetitive DNA sequences that can self-propagate in the human genome by using a ‘copy-and-paste’ mechanism in which an intermediate RNA molecule is reverse-transcribed to make a new genomic insertion.
- Synthetic locus control regions
-
Reporter systems that can be designed to reflect which transcriptional programmes and signalling pathways are active in cancer cells.
- The toxin–antitoxin system
-
A gene pair ubiquitous in prokaryotes which may mediate growth arrest when the toxin is expressed in excess of its cognate antitoxin, leading to tolerance.
- Translesion synthesis
-
A DNA damage tolerance mechanism that uses error-prone DNA polymerases to proceed with DNA replication, despite the presence of unrepaired DNA lesions.
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Russo, M., Chen, M., Mariella, E. et al. Cancer drug-tolerant persister cells: from biological questions to clinical opportunities. Nat Rev Cancer 24, 694–717 (2024). https://doi.org/10.1038/s41568-024-00737-z
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DOI: https://doi.org/10.1038/s41568-024-00737-z
