Abstract
Drug-tolerant persister (DTP) cell populations were originally discovered in antibiotic-resistant bacterial biofilms. Similar populations with comparable features have since been identified among cancer cells and have been linked with treatment resistance that lacks an underlying genomic alteration. Research over the past decade has improved our understanding of the biological roles of DTP cells in cancer, although clinical knowledge of the role of these cells in treatment resistance remains limited. Nonetheless, targeting this population is anticipated to provide new treatment opportunities. In this Perspective, we aim to provide a clear definition of the DTP phenotype, discuss the underlying characteristics of these cells, their biomarkers and vulnerabilities, and encourage further research on DTP cells that might improve our understanding and enable the development of more effective anticancer therapies.
Key points
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Drug-tolerant persister (DTP) cells are phenotypically heterogeneous, with diverse characteristics such as slow-proliferating or quiescent phenotypes, and a range of metabolic adaptations, cell identity switches and immune-evasion mechanisms. The specific traits expressed depend on the type of cancer and the treatment received.
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DTP cells arise stochastically. All cancer cells have the potential to enter a drug-tolerant state depending on their initial adaptive response to treatment.
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The DTP cell phenotype is transient and does not reflect the presence of resistance mutations. These cells can either produce drug-sensitive progeny or evolve towards irreversible, acquired resistance mediated by acquired genomic alterations.
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DTP cells emerge in tumours that initially respond to systemic anticancer therapies and might not be involved in disease recurrence following local therapies such as surgery. Incomplete responses to systemic therapies might reflect the coexistence of several distinct populations of resistant cancer cells, including dormant tumour cells, cancer stem cells, clones harbouring primary resistance and DTPs.
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No universally accepted biomarkers enabling the identification of DTP cells currently exist. The roles of DTP cells should be investigated in the context of specific clinical scenarios to facilitate their optimal application in precision oncology.
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References
Saini, K. S. & Twelves, C. Determining lines of therapy in patients with solid cancers: a proposed new systematic and comprehensive framework. Br. J. Cancer 125, 155–163 (2021).
Soria, J. C. et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N. Engl. J. Med. 378, 113–125 (2018).
Westover, D., Zugazagoitia, J., Cho, B. C., Lovly, C. M. & Paz-Ares, L. Mechanisms of acquired resistance to first- and second-generation EGFR tyrosine kinase inhibitors. Ann. Oncol. 29 (Suppl. 1), i10–i19 (2018).
Long, G. V. et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N. Engl. J. Med. 377, 1813–1823 (2017).
Dummer, R. et al. Five-year analysis of adjuvant dabrafenib plus trametinib in stage III Melanoma. N. Engl. J. Med. 383, 1139–1148 (2020).
Burnett, A., Wetzler, M. & Lowenberg, B. Therapeutic advances in acute myeloid leukemia. J. Clin. Oncol. 29, 487–494 (2011).
Roth, B. J. et al. Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small-cell lung cancer: a phase III trial of the Southeastern Cancer Study Group. J. Clin. Oncol. 10, 282–291 (1992).
Rudin, C. M., Brambilla, E., Faivre-Finn, C. & Sage, J. Small-cell lung cancer. Nat. Rev. Dis. Prim. 7, 3 (2021).
Shen, S., Vagner, S. & Robert, C. Persistent cancer cells: the deadly survivors. Cell 183, 860–874 (2020).
Luskin, M. R., Murakami, M. A., Manalis, S. R. & Weinstock, D. M. Targeting minimal residual disease: a path to cure? Nat. Rev. Cancer 18, 255–263 (2018).
Vallette, F. M. et al. Dormant, quiescent, tolerant and persister cells: four synonyms for the same target in cancer. Biochem. Pharmacol. 162, 169–176 (2019).
Risson, E., Nobre, A. R., Maguer-Satta, V. & Aguirre-Ghiso, J. A. The current paradigm and challenges ahead for the dormancy of disseminated tumor cells. Nat. Cancer 1, 672–680 (2020).
Batlle, E. & Clevers, H. Cancer stem cells revisited. Nat. Med. 23, 1124–1134 (2017).
Aguirre-Ghiso, J. A. Models, mechanisms and clinical evidence for cancer dormancy. Nat. Rev. Cancer 7, 834–846 (2007).
Phan, T. G. & Croucher, P. I. The dormant cancer cell life cycle. Nat. Rev. Cancer 20, 398–411 (2020).
Valent, P. et al. Cancer stem cell definitions and terminology: the devil is in the details. Nat. Rev. Cancer 12, 767–775 (2012).
Beck, B. & Blanpain, C. Unravelling cancer stem cell potential. Nat. Rev. Cancer 13, 727–738 (2013).
Malladi, S. et al. Metastatic latency and immune evasion through autocrine inhibition of WNT. Cell 165, 45–60 (2016).
Albrengues, J. et al. Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice. Science 361, eaao4227 (2018).
Sharma, S. V. et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141, 69–80 (2010).
Ramirez, M. et al. Diverse drug-resistance mechanisms can emerge from drug-tolerant cancer persister cells. Nat. Commun. 7, 10690 (2016).
Harbeck, N. et al. De-escalation strategies in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (BC): final analysis of the West German Study Group Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early BC HER2- and Hormone Receptor-Positive Phase II Randomized Trial — efficacy, safety, and predictive markers for 12 weeks of neoadjuvant trastuzumab emtansine with or without endocrine therapy (ET) versus trastuzumab plus ET. J. Clin. Oncol. 35, 3046–3054 (2017).
Bigger, J. W. Treatment of staphylococcal infections with penicillin by intermittent sterilisation. Lancet 244, 3 (1944).
Balaban, N. Q. et al. Definitions and guidelines for research on antibiotic persistence. Nat. Rev. Microbiol. 17, 441–448 (2019).
Urbaniec, J., Xu, Y., Hu, Y., Hingley-Wilson, S. & McFadden, J. Phenotypic heterogeneity in persisters: a novel ‘hunker’ theory of persistence. FEMS Microbiol. Rev. 46, fuab042 (2022).
Russo, M., Sogari, A. & Bardelli, A. Adaptive evolution: how bacteria and cancer cells survive stressful conditions and drug treatment. Cancer Discov. 11, 1886–1895 (2021).
Shen, S. et al. An epitranscriptomic mechanism underlies selective mRNA translation remodelling in melanoma persister cells. Nat. Commun. 10, 5713 (2019).
Rambow, F. et al. Toward minimal residual disease-directed therapy in melanoma. Cell 174, 843–855.e19 (2018).
Biehs, B. et al. A cell identity switch allows residual BCC to survive Hedgehog pathway inhibition. Nature 562, 429–433 (2018).
Russo, M. et al. Adaptive mutability of colorectal cancers in response to targeted therapies. Science 366, 1473–1480 (2019).
Rehman, S. K. et al. Colorectal cancer cells enter a diapause-like DTP state to survive chemotherapy. Cell 184, 226–242.e21 (2021).
Alvarez-Varela, A. et al. Mex3a marks drug-tolerant persister colorectal cancer cells that mediate relapse after chemotherapy. Nat. Cancer 3, 1052–1070 (2022).
Risom, T. et al. Differentiation-state plasticity is a targetable resistance mechanism in basal-like breast cancer. Nat. Commun. 9, 3815 (2018).
Echeverria, G. V. et al. Resistance to neoadjuvant chemotherapy in triple-negative breast cancer mediated by a reversible drug-tolerant state. Sci. Transl. Med. 11, eaav0936 (2019).
Marsolier, J. et al. H3K27me3 conditions chemotolerance in triple-negative breast cancer. Nat. Genet. 54, 459–468 (2022).
Viale, A. et al. Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature 514, 628–632 (2014).
Liau, B. B. et al. Adaptive chromatin remodeling drives glioblastoma stem cell plasticity and drug tolerance. Cell Stem Cell 20, 233–246.e7 (2017).
Farge, T. et al. Chemotherapy-resistant human acute myeloid leukemia cells are not enriched for leukemic stem cells but require oxidative metabolism. Cancer Discov. 7, 716–735 (2017).
Salgia, R. & Kulkarni, P. The genetic/non-genetic duality of drug ‘resistance’ in cancer. Trends Cancer 4, 110–118 (2018).
Hayford, C. E. et al. A heterogeneous drug tolerant persister state in BRAF-mutant melanoma is characterized by ion channel dysregulation and susceptibility to ferroptosis. Preprint at bioRxiv, https://doi.org/10.1101/2022.02.03.479045 (2022).
Chang, C. A. et al. Ontogeny and vulnerabilities of drug-tolerant persisters in HER2+ breast cancer. Cancer Discov. 12, 1022–1045 (2022).
Roesch, A. et al. A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell 141, 583–594 (2010).
Roesch, A. et al. Overcoming intrinsic multidrug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1Bhigh cells. Cancer Cell 23, 811–825 (2013).
Kalkavan, H. et al. Sublethal cytochrome c release generates drug-tolerant persister cells. Cell 185, 3356–3374.e22 (2022).
Antoszczak, M. et al. Iron-sensitive prodrugs that trigger active ferroptosis in drug-tolerant pancreatic cancer cells. J. Am. Chem. Soc. 144, 11536–11545 (2022).
El-Kenawi, A. B. et al. Elevated methionine flux drives pyroptosis evasion in persister cancer cells. Cancer Res. 83, 14 (2023).
Dhimolea, E. et al. An embryonic diapause-like adaptation with suppressed myc activity enables tumor treatment persistence. Cancer Cell 39, 240–256.e11 (2021).
Oren, Y. et al. Cycling cancer persister cells arise from lineages with distinct programs. Nature 596, 576–582 (2021).
Aissa, A. F. et al. Single-cell transcriptional changes associated with drug tolerance and response to combination therapies in cancer. Nat. Commun. 12, 1628 (2021).
Hejna, M. et al. Reinduction therapy with the same cytostatic regimen in patients with advanced colorectal cancer. Br. J. Cancer 78, 760–764 (1998).
Simon, G. R. & Wagner, H. American College of Chest Physicians. Small cell lung cancer. Chest 123 (Suppl. 1), 259S–271S (2003).
Colombo, N. & Gore, M. Treatment of recurrent ovarian cancer relapsing 6-12 months post platinum-based chemotherapy. Crit. Rev. Oncol. Hematol. 64, 129–138 (2007).
Sartore-Bianchi, A. et al. Circulating tumor DNA to guide rechallenge with panitumumab in metastatic colorectal cancer: the phase 2 CHRONOS trial. Nat. Med. 28, 1612–1618 (2022).
Marine, J. C., Dawson, S. J. & Dawson, M. A. Non-genetic mechanisms of therapeutic resistance in cancer. Nat. Rev. Cancer 20, 743–756 (2020).
Cabanos, H. F. & Hata, A. N. Emerging insights into targeted therapy-tolerant persister cells in cancer.Cancers 13, 2666 (2021).
Dhanyamraju, P. K., Schell, T. D., Amin, S. & Robertson, G. P. Drug-tolerant persister cells in cancer therapy resistance. Cancer Res. 82, 2503–2514 (2022).
Naumov, G. N. et al. Ineffectiveness of doxorubicin treatment on solitary dormant mammary carcinoma cells or late-developing metastases. Breast Cancer Res. Treat. 82, 199–206 (2003).
Min, M. & Spencer, S. L. Spontaneously slow-cycling subpopulations of human cells originate from activation of stress-response pathways. PLoS Biol. 17, e3000178 (2019).
Wiecek, A. J. et al. Genomic hallmarks and therapeutic implications of G0 cell cycle arrest in cancer. Genome Biol. 24, 128 (2023).
Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007 (2007).
Fujii, M. & Sato, T. Defining the role of Lgr5+ stem cells in colorectal cancer: from basic research to clinical applications. Genome Med. 9, 66 (2017).
Aibar, S. et al. SCENIC: single-cell regulatory network inference and clustering. Nat. Methods 14, 1083–1086 (2017).
Eyler, C. E. et al. Single-cell lineage analysis reveals genetic and epigenetic interplay in glioblastoma drug resistance. Genome Biol. 21, 174 (2020).
Recasens, A. et al. Global phosphoproteomics reveals DYRK1A regulates CDK1 activity in glioblastoma cells. Cell Death Discov. 7, 81 (2021).
Sadasivam, S. & DeCaprio, J. A. The DREAM complex: master coordinator of cell cycle-dependent gene expression. Nat. Rev. Cancer 13, 585–595 (2013).
MacDonald, J. et al. A systematic analysis of negative growth control implicates the DREAM complex in cancer cell dormancy. Mol. Cancer Res. 15, 371–381 (2017).
Shen, S. et al. Melanoma persister cells are tolerant to BRAF/MEK inhibitors via ACOX1-mediated fatty acid oxidation. Cell Rep. 33, 108421 (2020).
Zhang, Z. et al. Inhibition of NPC1L1 disrupts adaptive responses of drug-tolerant persister cells to chemotherapy. EMBO Mol. Med. 14, e14903 (2022).
Gerosa, L. et al. Receptor-driven ERK pulses reconfigure MAPK signaling and enable persistence of drug-adapted BRAF-mutant melanoma cells. Cell Syst. 11, 478–494.e9 (2020).
Russo, M. et al. A modified fluctuation-test framework characterizes the population dynamics and mutation rate of colorectal cancer persister cells. Nat. Genet. 54, 976–984 (2022).
Luria, S. E., & Delbrück, M. Mutations of bacteria from virus sensitivity to virus resistance. Genetics 28, 491–511 (1943).
Shaffer, S. M. et al. Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance. Nature 546, 431–435 (2017).
Baselga, J. et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 379, 633–640 (2012).
Moyed, H. S. & Bertrand, K. P. hipA, a newly recognized gene of Escherichia coli K-12 that affects frequency of persistence after inhibition of murein synthesis. J. Bacteriol. 155, 768–775 (1983).
Jacob Berger, A. et al. IRS1 phosphorylation underlies the non-stochastic probability of cancer cells to persist during EGFR inhibition therapy. Nat. Cancer 2, 1055–1070 (2021).
Barria, A., Muller, D., Derkach, V., Griffith, L. C. & Soderling, T. R. Regulatory phosphorylation of AMPA-type glutamate receptors by CaM-KII during long-term potentiation. Science 276, 2042–2045 (1997).
Menon, D. R. et al. A stress-induced early innate response causes multidrug tolerance in melanoma. Oncogene 34, 4545 (2015).
Guler, G. D. et al. Repression of stress-induced LINE-1 expression protects cancer cell subpopulations from lethal drug exposure. Cancer Cell 32, 221–237.e13 (2017).
Joers, A. & Tenson, T. Growth resumption from stationary phase reveals memory in Escherichia coli cultures. Sci. Rep. 6, 24055 (2016).
Riber, L. & Hansen, L. H. Epigenetic memories: the hidden drivers of bacterial persistence? Trends Microbiol. 29, 190–194 (2021).
Albeck, J. G. et al. Quantitative analysis of pathways controlling extrinsic apoptosis in single cells. Mol. Cell 30, 11–25 (2008).
Tait, S. W. et al. Resistance to caspase-independent cell death requires persistence of intact mitochondria. Dev. Cell 18, 802–813 (2010).
Oliver, L. et al. Constitutive presence of cytochrome c in the cytosol of a chemoresistant leukemic cell line. Apoptosis 10, 277–287 (2005).
Wang, W. et al. CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy. Nature 569, 270–274 (2019).
Sehgal, K. et al. Dynamic single-cell RNA sequencing identifies immunotherapy persister cells following PD-1 blockade. J. Clin. Invest. 131, e135038 (2021).
Miao, Y. et al. Adaptive immune resistance emerges from tumor-initiating stem cells. Cell 177, 1172–1186.e14 (2019).
Nilsson, M. B. et al. CD70 is a therapeutic target upregulated in EMT-associated EGFR tyrosine kinase inhibitor resistance. Cancer Cell 41, 340–355.e6 (2023).
Flieswasser, T. et al. Screening a broad range of solid and haematological tumour types for CD70 expression using a uniform IHC methodology as potential patient stratification method. Cancers 11, 1611 (2019).
Johnson, P. J. & Levin, B. R. Pharmacodynamics, population dynamics, and the evolution of persistence in Staphylococcus aureus. PLoS Genet. 9, e1003123 (2013).
Nam, A. et al. Dynamic phenotypic switching and group behavior help non-small cell lung cancer cells evade chemotherapy. Biomolecules 12, 8 (2021).
Noronha, A. et al. AXL and error-prone DNA replication confer drug resistance and offer strategies to treat EGFR-mutant lung cancer. Cancer Discov. 12, 2666–2683 (2022).
Stelter, P. & Ulrich, H. D. Control of spontaneous and damage-induced mutagenesis by SUMO and ubiquitin conjugation. Nature 425, 188–191 (2003).
Hata, A. N. et al. Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nat. Med. 22, 262–269 (2016).
Schmitt, M. et al. Colon tumour cell death causes mTOR dependence by paracrine P2X4 stimulation. Nature 612, 347–353 (2022).
Enari, M. et al. A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 391, 43–50 (1998).
Williams, A. F. et al. Abstract 99: Apoptotic DNase DFFB mediates cancer persister cell mutagenesis and acquired drug resistance. Cancer Res. 83 (Suppl. 7), 99 (2023).
Ichim, G. et al. Limited mitochondrial permeabilization causes DNA damage and genomic instability in the absence of cell death. Mol. Cell 57, 860–872 (2015).
Lovric, M. M. & Hawkins, C. J. TRAIL treatment provokes mutations in surviving cells. Oncogene 29, 5048–5060 (2010).
Velazquez, E. R., Aerts, H. J., Oberije, C., De Ruysscher, D. & Lambin, P. Prediction of residual metabolic activity after treatment in NSCLC patients. Acta Oncol. 49, 1033–1039 (2010).
Zamagni, E. et al. Impact of minimal residual disease standardised assessment by FDG-PET/CT in transplant-eligible patients with newly diagnosed multiple myeloma enrolled in the imaging sub-study of the FORTE trial. EClinicalMedicine 60, 102017 (2023).
Valkema, M. J. et al. Accuracy of 18F-FDG PET/CT in predicting residual disease after neoadjuvant chemoradiotherapy for esophageal cancer. J. Nucl. Med. 60, 1553–1559 (2019).
Lue, H. W. et al. Metabolic reprogramming ensures cancer cell survival despite oncogenic signaling blockade. Genes Dev. 31, 2067–2084 (2017).
Hangauer, M. J. et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature 551, 247–250 (2017).
Muller, S. et al. CD44 regulates epigenetic plasticity by mediating iron endocytosis. Nat. Chem. 12, 929–938 (2020).
Chauvistre, H. et al. Persister state-directed transitioning and vulnerability in melanoma. Nat. Commun. 13, 3055 (2022).
Jiang, H. et al. Ferrous iron-activatable drug conjugate achieves potent MAPK blockade in KRAS-driven tumors. J. Exp. Med. 219, e20210739 (2022).
Behr, S. C. et al. Targeting iron metabolism in high-grade glioma with 68Ga-citrate PET/MR. JCI Insight 3, e93999 (2018).
Behr, S. C. et al. A feasibility study showing [68Ga]citrate PET detects prostate cancer. Mol. Imaging Biol. 18, 946–951 (2016).
Aparici, C. M. et al. Imaging hepatocellular carcinoma with 68Ga-citrate PET: first clinical experience. Mol. Imaging 16, 1536012117723256 (2017).
Promteangtrong, C. et al. Head-to-head comparison of 68Ga-FAPI-46 and 18F-FDG PET/CT for evaluation of head and neck squamous cell carcinoma: a single-center exploratory study. J. Nucl. Med. 63, 1155–1161 (2022).
Spick, C., Herrmann, K. & Czernin, J. Evaluation of prostate cancer with 11C-acetate PET/CT. J. Nucl. Med. 57 (Suppl. 3), 30S–37S (2016).
Park, S. et al. 11C-acetate and 18F-fluorodeoxyglucose positron emission tomography/computed tomography dual imaging for the prediction of response and prognosis after transarterial chemoembolization. Medicine 97, e12311 (2018).
Camidge, D. R. et al. Brigatinib versus crizotinib in ALK-positive non-small-cell lung cancer. N. Engl. J. Med. 379, 2027–2039 (2018).
Adler, S. et al. Minimum lesion detectability as a measure of PET system performance. EJNMMI Phys. 4, 13 (2017).
Cohen, S. J. et al. Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J. Clin. Oncol. 26, 3213–3221 (2008).
Krebs, M. G. et al. Molecular analysis of circulating tumour cells-biology and biomarkers. Nat. Rev. Clin. Oncol. 11, 129–144 (2014).
Lawrence, R., Watters, M., Davies, C. R., Pantel, K. & Lu, Y. J. Circulating tumour cells for early detection of clinically relevant cancer. Nat. Rev. Clin. Oncol. 20, 487–500 (2023).
Ko, J. M. et al. Clinical utility of serial analysis of circulating tumour cells for detection of minimal residual disease of metastatic nasopharyngeal carcinoma. Br. J. Cancer 123, 114–125 (2020).
Brown, H. K. et al. Characterization of circulating tumor cells as a reflection of the tumor heterogeneity: myth or reality? Drug Discov. Today 24, 763–772 (2019).
Gabriel, M. T., Calleja, L. R., Chalopin, A., Ory, B. & Heymann, D. Circulating tumor cells: a review of non-EpCAM-based approaches for cell enrichment and isolation. Clin. Chem. 62, 571–581 (2016).
Andreopoulou, E. et al. Comparison of assay methods for detection of circulating tumor cells in metastatic breast cancer: AdnaGen AdnaTest BreastCancer Select/DetectTM versus Veridex CellSearchTM system. Int. J. Cancer 130, 1590–1597 (2012).
Feng, W. W. et al. CD36-mediated metabolic rewiring of breast cancer cells promotes resistance to HER2-targeted therapies. Cell Rep. 29, 3405–3420.e5 (2019).
Pascual, G. et al. Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature 541, 41–45 (2017).
Vendramin, R. et al. Activation of the integrated stress response confers vulnerability to mitoribosome-targeting antibiotics in melanoma. J. Exp. Med. 218, e20210571 (2021).
Chuang, C. H. et al. Molecular definition of a metastatic lung cancer state reveals a targetable CD109-Janus kinase-Stat axis. Nat. Med. 23, 291–300 (2017).
Franco, S. S. et al. In vitro models of cancer stem cells and clinical applications. BMC Cancer 16, 738 (2016).
Kantara, C. et al. Methods for detecting circulating cancer stem cells (CCSCs) as a novel approach for diagnosis of colon cancer relapse/metastasis. Lab. Invest. 95, 100–112 (2015).
Song, C. et al. Recurrent tumor cell-intrinsic and -extrinsic alterations during mapki-induced melanoma regression and early adaptation. Cancer Discov. 7, 1248–1265 (2017).
Newman, A. M. et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat. Med. 20, 548–554 (2014).
Jee, J. et al. Overall survival with circulating tumor DNA-guided therapy in advanced non-small-cell lung cancer. Nat. Med. 28, 2353–2363 (2022).
Tie, J. et al. Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer. N. Engl. J. Med. 386, 2261–2272 (2022).
Zhang, J. T. et al. Longitudinal undetectable molecular residual disease defines potentially cured population in localized non-small cell lung cancer. Cancer Discov. 12, 1690–1701 (2022).
Abbosh, C. et al. Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA. Nature 616, 553–562 (2023).
Diehl, F. et al. Detection and quantification of mutations in the plasma of patients with colorectal tumors. Proc. Natl Acad. Sci. USA 102, 16368–16373 (2005).
Sadeh, R. et al. ChIP-seq of plasma cell-free nucleosomes identifies gene expression programs of the cells of origin. Nat. Biotechnol. 39, 586–598 (2021).
Tellez-Gabriel, M. et al. Circulating tumor cell-derived pre-clinical models for personalized medicine. Cancers 11, 19 (2018).
Maynard, A. et al. Therapy-induced evolution of human lung cancer revealed by single-cell RNA sequencing. Cell 182, 1232–1251.e22 (2020).
Schwartz, L. H. et al. RECIST 1.1-update and clarification: from the RECIST committee. Eur. J. Cancer 62, 132–137 (2016).
Vogelstein, B. et al. Cancer genome landscapes. Science 339, 1546–1558 (2013).
Marusyk, A., Janiszewska, M. & Polyak, K. Intratumor heterogeneity: the rosetta stone of therapy resistance. Cancer Cell 37, 471–484 (2020).
Goyal, Y. et al. Diverse clonal fates emerge upon drug treatment of homogeneous cancer cells.Nature 620, 651–659 (2023).
Zhao, B. et al. Exploiting temporal collateral sensitivity in tumor clonal evolution. Cell 165, 234–246 (2016).
Rodriguez, R., Schreiber, S. L. & Conrad, M. Persister cancer cells: iron addiction and vulnerability to ferroptosis. Mol. Cell 82, 728–740 (2022).
Dos Santos, A. F., Fazeli, G., Xavier da Silva, T. N. & Friedmann Angeli, J. P. Ferroptosis: mechanisms and implications for cancer development and therapy response. Trends Cell Biol. https://doi.org/10.1016/j.tcb.2023.04.005 (2023).
Dixon, S. J. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060–1072 (2012).
Shimada, K. et al. Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis. Nat. Chem. Biol. 12, 497–503 (2016).
Viswanathan, V. S. et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 547, 453–457 (2017).
Ding, C. C. et al. MESH1 is a cytosolic NADPH phosphatase that regulates ferroptosis. Nat. Metab. 2, 270–277 (2020).
Olsen, N. J. & Stein, C. M. New drugs for rheumatoid arthritis. N. Engl. J. Med. 350, 2167–2179 (2004).
Vinogradova, M. et al. An inhibitor of KDM5 demethylases reduces survival of drug-tolerant cancer cells. Nat. Chem. Biol. 12, 531–538 (2016).
Hinohara, K. et al. KDM5 histone demethylase activity links cellular transcriptomic heterogeneity to therapeutic resistance. Cancer Cell 34, 939–953.e9 (2018).
Olsen, E. A. et al. Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J. Clin. Oncol. 25, 3109–3115 (2007).
US FDA. Drug Approval Package https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021991s000_zolinzatoc.cfm (2006).
Ramalingam, S. S. et al. Carboplatin and paclitaxel in combination with either vorinostat or placebo for first-line therapy of advanced non-small-cell lung cancer. J. Clin. Oncol. 28, 56–62 (2010).
Criscione, S. W. et al. The landscape of therapeutic vulnerabilities in EGFR inhibitor osimertinib drug tolerant persister cells. NPJ Precis. Oncol. 6, 95 (2022).
Karras, P. et al. A cellular hierarchy in melanoma uncouples growth and metastasis. Nature 610, 190–198 (2022).
Marin-Bejar, O. et al. Evolutionary predictability of genetic versus nongenetic resistance to anticancer drugs in melanoma. Cancer Cell 39, 1135–1149.e8 (2021).
Kurppa, K. J. et al. Treatment-induced tumor dormancy through YAP-mediated transcriptional reprogramming of the apoptotic pathway. Cancer Cell 37, 104–122.e12 (2020).
Ruscetti, M. et al. NK cell-mediated cytotoxicity contributes to tumor control by a cytostatic drug combination. Science 362, 1416–1422 (2018).
Ruscetti, M. et al. Senescence-induced vascular remodeling creates therapeutic vulnerabilities in pancreas cancer. Cell 181, 424–441.e21 (2020).
Fane, M. E. et al. Stromal changes in the aged lung induce an emergence from melanoma dormancy. Nature 606, 396–405 (2022).
Wang, C. et al. Inducing and exploiting vulnerabilities for the treatment of liver cancer. Nature 574, 268–272 (2019).
Iwai, K. et al. A CDC7 inhibitor sensitizes DNA-damaging chemotherapies by suppressing homologous recombination repair to delay DNA damage recovery. Sci. Adv. 7, eabf0197 (2021).
Enriquez-Navas, P. M. et al. Exploiting evolutionary principles to prolong tumor control in preclinical models of breast cancer. Sci. Transl. Med. 8, 327ra24 (2016).
Labrie, M., Brugge, J. S., Mills, G. B. & Zervantonakis, I. K. Therapy resistance: opportunities created by adaptive responses to targeted therapies in cancer. Nat. Rev. Cancer 22, 323–339 (2022).
Hughes, D. & Andersson, D. I. Evolutionary consequences of drug resistance: shared principles across diverse targets and organisms. Nat. Rev. Genet. 16, 459–471 (2015).
Kuczynski, E. A., Sargent, D. J., Grothey, A. & Kerbel, R. S. Drug rechallenge and treatment beyond progression–implications for drug resistance. Nat. Rev. Clin. Oncol. 10, 571–587 (2013).
Kavran, A. J. et al. Intermittent treatment of BRAF(V600E) melanoma cells delays resistance by adaptive resensitization to drug rechallenge. Proc. Natl Acad. Sci. USA 119, e2113535119 (2022).
Algazi, A. P. et al. Continuous versus intermittent BRAF and MEK inhibition in patients with BRAF-mutated melanoma: a randomized phase 2 trial. Nat. Med. 26, 1564–1568 (2020).
Gonzalez-Cao, M. et al. Intermittent BRAF inhibition in advanced BRAF mutated melanoma results of a phase II randomized trial. Nat. Commun. 12, 7008 (2021).
Brown, J. E. et al. Temporary treatment cessation versus continuation of first-line tyrosine kinase inhibitor in patients with advanced clear cell renal cell carcinoma (STAR): an open-label, non-inferiority, randomised, controlled, phase 2/3 trial. Lancet Oncol. 24, 213–227 (2023).
Hussain, M. et al. Intermittent versus continuous androgen deprivation in prostate cancer. N. Engl. J. Med. 368, 1314–1325 (2013).
Zhang, J., Cunningham, J. J., Brown, J. S. & Gatenby, R. A. Integrating evolutionary dynamics into treatment of metastatic castrate-resistant prostate cancer. Nat. Commun. 8, 1816 (2017).
Lewis, K. Persister cells. Ann. Rev. Microbiol. 64, 357–372 (2010).
Cara, S. & Tannock, I. F. Retreatment of patients with the same chemotherapy: implications for clinical mechanisms of drug resistance. Ann. Oncol. 12, 23–27 (2001).
Muss, H. B., Smith, L. R. & Cooper, M. R. Tamoxifen rechallenge: response to tamoxifen following relapse after adjuvant chemohormonal therapy for breast cancer. J. Clin. Oncol. 5, 1556–1558 (1987).
Palmieri, C. et al. Rechallenging with anthracyclines and taxanes in metastatic breast cancer. Nat. Rev. Clin. Oncol. 7, 561–574 (2010).
Acknowledgements
S.S. acknowledges grant support from the National Natural Science Foundation of China (grant No. 82172794) and from the National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University (grant No. Y2022JC002). C.R. thanks S. Bazin, O. and C. Courtin, Ensemble Contre le Mélanome, the Foundation Crédit Mutuel, Foundation Carrefour and the association Vaincre le Mélanome for their ongoing research funding support.
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C.R. has acted as a consultant for Astra Zeneca, BMS, MSD, Pfizer, Pierre Fabre, Roche, and Sanofi and is a co-founder of Ribonexus. Y.P., L.L., H.P., L.L., D.H., F.V. and S.S. declare no competing interests.
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Pu, Y., Li, L., Peng, H. et al. Drug-tolerant persister cells in cancer: the cutting edges and future directions. Nat Rev Clin Oncol 20, 799–813 (2023). https://doi.org/10.1038/s41571-023-00815-5
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DOI: https://doi.org/10.1038/s41571-023-00815-5
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