https://doi.org/10.53941/ijddp.2025.100011
Zhang, W., Chattrakarn, S., Chen, F., Chai, H., Maranga, M., & Zhang, J. Targeting Cancer Drug-Tolerant Persister Cells in Minimal Residual Disease. International Journal of Drug Discovery and Pharmacology. 2025, 4(2), 100011. doi: https://doi.org/10.53941/ijddp.2025.100011
Volume 4, Issue 2, 2025
Copyright (c) 2025 by the authors.
Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Cancer cells that survive therapeutic drug pressure are a significant cause of disease relapse and progression, impeding curative cancer treatment. Drug-triggered Darwinian selection and the emergence of subclones harbouring specific mutations that confer resistance have been well documented and extensively studied. However, these genetic alterations, while important, do not fully explain clinical observations where some patients, after a drug holiday, regain sensitivity to the same treatment despite previous disease progression. This phenomenon highlights the possibility that drug resistance may not solely rely on genetic mutations but could also involve reversible, non-genetic mechanisms. Recent studies have highlighted the existence of drug-tolerant persister cells (DTPs), a subpopulation of cancer cells that can survive short-term therapeutic pressure without acquiring resistance-associated genetic alterations. These cells exhibit a temporary yet reversible tolerance to the initial treatment while also acquiring cross-tolerance to other anti-cancer therapies. The presence of DTPs underscores a dynamic and complex plasticity in tumours, wherein cancer cells can utilise epigenetic rewiring, metabolic reprogramming, and specific signalling pathways to transit between drug-tolerant and drug-sensitive states to adapt to environmental pressures. Furthermore, this adaptive resilience enables DTPs to act as a reservoir for the development of genetically stable resistance, resulting in cancer therapy failure and eventual relapse. In this mini-review, we examine recent evidence on DTPs to provide an overview of their characteristics, development, and survival mechanisms.

Keywords:

minimal residual disease drug-tolerant persister cells drug resistance drug tolerance ferroptosis

References

  1. Sattler, M.; Mambetsariev, I.; Fricke, J.; et al. A Closer Look at EGFR Inhibitor Resistance in Non-Small Cell Lung Cancer through the Lens of Precision Medicine. J. Clin. Med. 2023, 12, 1936. https://doi.org/10.3390/jcm12051936.
  2. Kuczynski, E.A.; Sargent, D.J.; Grothey, A.; et al. Drug rechallenge and treatment beyond progression--implications for drug resistance. Nat. Rev. Clin. Oncol. 2013, 10, 571–587. https://doi.org/10.1038/nrclinonc.2013.158.
  3. Sharma, S.V.; Lee, D.Y.; Li, B.; et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 2010, 141, 69–80. https://doi.org/10.1016/j.cell.2010.02.027.
  4. He, J.; Qiu, Z.; Fan, J.; et al. Drug tolerant persister cell plasticity in cancer: A revolutionary strategy for more effective anticancer therapies. Signal Transduct. Target. Ther. 2024, 9, 209. https://doi.org/10.1038/s41392-024-01891-4.
  5. Shen, S.; Faouzi, S.; Bastide, A.; et al. An epitranscriptomic mechanism underlies selective mRNA translation remodelling in melanoma persister cells. Nat. Commun. 2019, 10, 5713. https://doi.org/10.1038/s41467-019-13360-6.
  6. Echeverria, G.V.; Ge, Z.; Seth, S.; et al. Resistance to neoadjuvant chemotherapy in triple-negative breast cancer mediated by a reversible drug-tolerant state. Sci. Transl. Med. 2019, 11, eaav0936. https://doi.org/10.1126/scitranslmed.aav0936.
  7. Criscione, S.W.; Martin, M.J.; Oien, D.B.; et al. The landscape of therapeutic vulnerabilities in EGFR inhibitor osimertinib drug tolerant persister cells. NPJ Precis. Oncol. 2022, 6, 95. https://doi.org/10.1038/s41698-022-00337-w.
  8. Ogden, S.; Carys, K.; Ahmed, I.; et al. Regulatory chromatin rewiring promotes metabolic switching during adaptation to oncogenic receptor tyrosine kinase inhibition. Oncogene 2022, 41, 4808–4822. https://doi.org/10.1038/s41388-022-02465-w.
  9. Kurppa, K.J.; Liu, Y.; To, C.; et al. Treatment-Induced Tumor Dormancy through YAP-Mediated Transcriptional Reprogramming of the Apoptotic Pathway. Cancer Cell 2020, 37, 104–122.e12. https://doi.org/10.1016/j.ccell.2019.12.006.
  10. Dhimolea, E.; de Matos Simoes, R.; Kansara, D.; et al. An Embryonic Diapause-like Adaptation with Suppressed Myc Activity Enables Tumor Treatment Persistence. Cancer Cell 2021, 39, 240–256.e11. https://doi.org/10.1016/j.ccell.2020.12.002.
  11. Rehman, S.K.; Haynes, J.; Collignon, E.; et al. Colorectal Cancer Cells Enter a Diapause-like DTP State to Survive Chemotherapy. Cell. 2021, 184, 226–242.e21. https://doi.org/10.1016/j.cell.2020.11.018.
  12. Rosano, D.; Sofyali, E.; Dhiman, H.; et al. Long-term Multimodal Recording Reveals Epigenetic Adaptation Routes in Dormant Breast Cancer Cells. Cancer Discov. 2024, 14, 866–889. https://doi.org/10.1158/2159-8290.CD-23-1161.
  13. Zhang, X.; Ma, Y.; Ma, J.; et al. Glutathione Peroxidase 4 as a Therapeutic Target for Anti-Colorectal Cancer Drug-Tolerant Persister Cells. Front. Oncol. 2022, 12, 913669. https://doi.org/10.3389/fonc.2022.913669.
  14. Fox, D.B.; Garcia, N.M.G.; McKinney, B.J.; et al. NRF2 activation promotes the recurrence of dormant tumour cells through regulation of redox and nucleotide metabolism. Nat. Metab. 2020, 2, 318–334. https://doi.org/10.1038/s42255-020-0191-z.
  15. Oren, Y.; Tsabar, M.; Cuoco, M.S.; et al. Cycling cancer persister cells arise from lineages with distinct programs. Nature 2021, 596, 576–582. https://doi.org/10.1038/s41586-021-03796-6.
  16. Cohen, A.A.; Geva-Zatorsky, N.; Eden, E.; et al. Dynamic proteomics of individual cancer cells in response to a drug. Science 2008, 322, 1511–1516. https://doi.org/10.1126/science.1160165.
  17. Bellio, C.; Emperador, M.; Castellano, P.; et al. GDF15 Is an Eribulin Response Biomarker also Required for Survival of DTP Breast Cancer Cells. Cancers 2022, 14, 2562. https://doi.org/10.3390/cancers14102562.
  18. Chang, C.A.; Jen, J.; Jiang, S.; et al. Ontogeny and Vulnerabilities of Drug-Tolerant Persisters in HER2+ Breast Cancer. Cancer Discov. 2022, 12, 1022–1045. https://doi.org/10.1158/2159-8290.CD-20-1265.
  19. Chen, M.; Mainardi, S.; Lieftink, C.; et al. Targeting of vulnerabilities of drug-tolerant persisters identified through functional genetics delays tumor relapse. Cell Rep. Med. 2024, 5, 101471. https://doi.org/10.1016/j.xcrm.2024.101471.
  20. Momeny, M.; Tienhaara, M.; Sharma, M.; et al. DUSP6 inhibition overcomes neuregulin/HER3-driven therapy tolerance in HER2+ breast cancer. EMBO Mol. Med. 2024, 16, 1603–1629. https://doi.org/10.1038/s44321-024-00088-0.
  21. Ramirez, M.; Rajaram, S.; Steininger, R.J.; et al. Diverse drug-resistance mechanisms can emerge from drug-tolerant cancer persister cells. Nat. Commun. 2016, 7, 10690. Published 2016 Feb 19. https://doi.org/10.1038/ncomms10690.
  22. França, G.S.; Baron, M.; King, B.R.; et al. Cellular adaptation to cancer therapy along a resistance continuum. Nature 2024, 631, 876–883. https://doi.org/10.1038/s41586-024-07690-9.
  23. Guler, G.D.; Tindell, C.A.; Pitti, R.; et al. Repression of Stress-Induced LINE-1 Expression Protects Cancer Cell Subpopulations from Lethal Drug Exposure. Cancer Cell 2017, 32, 221–237.e13. https://doi.org/10.1016/j.ccell.2017.07.002.
  24. Ravindran Menon, D.; Das, S.; Krepler, C.; et al. A stress-induced early innate response causes multidrug tolerance in melanoma. Oncogene 2015, 34, 4448–4459. https://doi.org/10.1038/onc.2014.372; Erratum in Oncogene 2015, 34, 4545. https://doi.org/10.1038/onc.2014.432.
  25. Liau, B.B.; Sievers, C.; Donohue, L.K.; et al. Adaptive Chromatin Remodeling Drives Glioblastoma Stem Cell Plasticity and Drug Tolerance. Cell Stem Cell 2017, 20, 233–246.e7. https://doi.org/10.1016/j.stem.2016.11.003.
  26. Vinogradova, M.; Gehling, V.S.; Gustafson, A.; et al. An inhibitor of KDM5 demethylases reduces survival of drug-tolerant cancer cells. Nat. Chem. Biol. 2016, 12, 531–538. https://doi.org/10.1038/nchembio.2085.
  27. Gupta, P.B.; Fillmore, C.M.; Jiang, G.; et al. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell 2011, 146, 633–644. https://doi.org/10.1016/j.cell.2011.07.026.
  28. Shaffer, S.M.; Dunagin, M.C.; Torborg, S.R.; et al. Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance. Nature 2017, 546, 431–435. https://doi.org/10.1038/nature22794.
  29. Spencer, S.L.; Gaudet, S.; Albeck, J.G.; et al. Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis. Nature 2009, 459, 428–432. https://doi.org/10.1038/nature08012.
  30. Dar, R.D.; Hosmane, N.N.; Arkin, M.R.; et al. Screening for noise in gene expression identifies drug synergies. Science 2014, 344, 1392–1396. https://doi.org/10.1126/science.1250220.
  31. Goyal, Y.; Busch, G.T.; Pillai, M.; et al. Diverse clonal fates emerge upon drug treatment of homogeneous cancer cells. Nature 2023, 620, 651–659. https://doi.org/10.1038/s41586-023-06342-8.
  32. Torre, E.A.; Arai, E.; Bayatpour, S.; et al. Genetic screening for single-cell variability modulators driving therapy resistance. Nat. Genet. 2021, 53, 76–85. https://doi.org/10.1038/s41588-020-00749-z.
  33. Roesch, A.; Vultur, A.; Bogeski, I.; et al. Overcoming intrinsic multidrug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1B (high) cells. Cancer Cell 2013, 23, 811–825. https://doi.org/10.1016/j.ccr.2013.05.003.
  34. Roesch, A.; Fukunaga-Kalabis, M.; Schmidt, E.C.; et al. A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell 2010, 141, 583–594. https://doi.org/10.1016/j.cell.2010.04.020.
  35. Kalkavan, H.; Chen, M.J.; Crawford, J.C.; et al. Sublethal cytochrome c release generates drug-tolerant persister cells. Cell 2022, 185, 3356–3374.e22. https://doi.org/10.1016/j.cell.2022.07.025.
  36. Iyer, D.P.; Khoei, H.H.; van der Weijden, V.A.; et al. mTOR activity paces human blastocyst stage developmental progression. Cell 2024. https://doi.org/10.1016/j.cell.2024.08.048.
  37. Dongre, A.; Weinberg, R.A. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat. Rev. Mol. Cell Biol. 2019, 20, 69–84. https://doi.org/10.1038/s41580-018-0080-4.
  38. Hata, A.N.; Niederst, M.J.; Archibald, H.L.; et al. Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nat. Med. 2016, 22, 262–269. https://doi.org/10.1038/nm.4040.
  39. Su, Y.; Wei, W.; Robert, L.; et al. Single-cell analysis resolves the cell state transition and signaling dynamics associated with melanoma drug-induced resistance. Proc. Natl. Acad. Sci. USA 2017, 114, 13679–13684. https://doi.org/10.1073/pnas.1712064115.
  40. Suda, K.; Tomizawa, K.; Fujii, M.; et al. Epithelial to mesenchymal transition in an epidermal growth factor receptor-mutant lung cancer cell line with acquired resistance to erlotinib. J. Thorac. Oncol. 2011, 6, 1152–1161. https://doi.org/10.1097/JTO.0b013e318216ee52.
  41. Song, K.A.; Niederst, M.J.; Lochmann, T.L.; et al. Epithelial-to-Mesenchymal Transition Antagonizes Response to Targeted Therapies in Lung Cancer by Suppressing BIM. Clin. Cancer Res. 2018, 24, 197–208. https://doi.org/10.1158/1078-0432.CCR-17-1577.
  42. Perillo, B.; Di Donato, M.; Pezone, A.; et al. ROS in cancer therapy: The bright side of the moon. Exp. Mol. Med. 2020, 52, 192–203. https://doi.org/10.1038/s12276-020-0384-2.
  43. Wang, R.; Mi, Y.; Ni, J.; et al. Identification of PRDX5 as A Target for The Treatment of Castration-Resistant Prostate Cancer. Adv. Sci. 2024, 11, e2304939. https://doi.org/10.1002/advs.202304939.
  44. Celeste, F.V.; Powers, S. Induction of Multiple Alternative Mitogenic Signaling Pathways Accompanies the Emergence of Drug-Tolerant Cancer Cells. Cancers 2024, 16, 1001. https://doi.org/10.3390/cancers16051001.
  45. Zhang, Z.; Qin, S.; Chen, Y.; et al. Inhibition of NPC1L1 disrupts adaptive responses of drug-tolerant persister cells to chemotherapy. EMBO Mol. Med. 2022, 14, e14903. https://doi.org/10.15252/emmm.202114903.
  46. Torrente, L.; DeNicola, G.M. Targeting NRF2 and Its Downstream Processes: Opportunities and Challenges. Annu. Rev. Pharmacol. Toxicol. 2022, 62, 279–300. https://doi.org/10.1146/annurev-pharmtox-052220-104025.
  47. He, F.; Antonucci, L.; Karin, M. NRF2 as a regulator of cell metabolism and inflammation in cancer. Carcinogenesis 2020, 41, 405–416. https://doi.org/10.1093/carcin/bgaa039.
  48. Tournier, C.; Zhang, W.; Chattrakarn, S.; et al. NRF2-Mediated Persistent Adaptation of Oesophageal Adenocarcinoma Cells to HER2 Inhibition. 2024. Available online: https://www.researchsquare.com/article/rs-4504280/v1(accessed on 1 October 2024). doi: 10.21203/rs.3.rs-4504280/v1
  49. Stockwell, B.R. Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. Cell. 2022, 185, 2401–2421. https://doi.org/10.1016/j.cell.2022.06.003.
  50. Hangauer, M.J.; Viswanathan, V.S.; Ryan, M.J.; et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature 2017, 551, 247–250. https://doi.org/10.1038/nature24297.
  51. Schwab, A.; Rao, Z.; Zhang, J.; et al. Zeb1 mediates EMT/plasticity-associated ferroptosis sensitivity in cancer cells by regulating lipogenic enzyme expression and phospholipid composition. Nat. Cell Biol. 2024, 26, 1470–1481. https://doi.org/10.1038/s41556-024-01464-1.
  52. Viswanathan, V.S.; Ryan, M.J.; Dhruv, H.D.; et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 2017, 547, 453–457. https://doi.org/10.1038/nature23007.
  53. Gotorbe, C.; Durivault, J.; Meira, W.; et al. Metabolic Rewiring toward Oxidative Phosphorylation Disrupts Intrinsic Resistance to Ferroptosis of the Colon Adenocarcinoma Cells. Antioxidants 2022, 11, 2412. https://doi.org/10.3390/antiox11122412.
  54. Zhang, Z.; Tan, Y.; Huang, C.; Wei, X. Redox signaling in drug-tolerant persister cells as an emerging therapeutic target. EBioMedicine 2023, 89, 104483. https://doi.org/10.1016/j.ebiom.2023.104483.
  55. Du, R.; Huang, C.; Liu, K.; et al. Targeting AURKA in Cancer: Molecular mechanisms and opportunities for Cancer therapy. Mol. Cancer 2021, 20, 15. https://doi.org/10.1186/s12943-020-01305-3.
  56. Anshabo, A.T.; Milne, R.; et al. CDK9: A Comprehensive Review of Its Biology, and Its Role as a Potential Target for Anti-Cancer Agents. Front. Oncol. 2021, 11, 678559. https://doi.org/10.3389/fonc.2021.678559.
  57. Hirata, E.; Girotti, M.R.; Viros, A.; et al. Intravital imaging reveals how BRAF inhibition generates drug-tolerant microenvironments with high integrin β1/FAK signaling. Cancer Cell 2015, 27, 574–588. https://doi.org/10.1016/j.ccell.2015.03.008.
  58. Obenauf, A.C.; Zou, Y.; Ji, A.L.; et al. Therapy-induced tumour secretomes promote resistance and tumour progression. Nature 2015, 520, 368–372. https://doi.org/10.1038/nature14336.
  59. Mancini, C.; Lori, G.; Pranzini, E.; et al. Metabolic challengers selecting tumor-persistent cells. Trends Endocrinol. Metab. 2024, 35, 263–276. https://doi.org/10.1016/j.tem.2023.11.005.
  60. Son, B.; Lee, S.; Youn, H.; et al. The role of tumor microenvironment in therapeutic resistance. Oncotarget. 2017, 8, 3933–3945. https://doi.org/10.18632/oncotarget.13907.
  61. Ebi, H. Drug-Tolerant Persister Cells after EGFR Tyrosine Kinase Inhibitor Treatment: Their Origin and the Influences from the Tumor Microenvironment. J. Thorac. Oncol. 2023, 18, 399–401. https://doi.org/10.1016/j.jtho.2022.12.010.
  62. Nakasone, E.S.; Askautrud, H.A.; Kees, T.; et al. Imaging tumor-stroma interactions during chemotherapy reveals contributions of the microenvironment to resistance. Cancer Cell 2012, 21, 488–503. https://doi.org/10.1016/j.ccr.2012.02.017.
  63. Junttila, M.R.; de Sauvage, F.J. Influence of tumour micro-environment heterogeneity on therapeutic response. Nature 2013, 501, 346–354. https://doi.org/10.1038/nature12626.
  64. Shen, S.; Vagner, S.; Robert, C. Persistent Cancer Cells: The Deadly Survivors. Cell 2020, 183, 860–874. https://doi.org/10.1016/j.cell.2020.10.027.
  65. Niu, N.; Shen, X.; Wang, Z.; et al. Tumor cell-intrinsic epigenetic dysregulation shapes cancer-associated fibroblasts heterogeneity to metabolically support pancreatic cancer. Cancer Cell 2024, 42, 869–884.e9. https://doi.org/10.1016/j.ccell.2024.03.005.
  66. Gunnarsson, E.B.; De, S.; Leder, K.; Foo, J. Understanding the role of phenotypic switching in cancer drug resistance. J. Theor. Biol. 2020, 490, 110162. https://doi.org/10.1016/j.jtbi.2020.110162.
  67. Russo, M.; Pompei, S.; Sogari, A.; et al. A modified fluctuation-test framework characterizes the population dynamics and mutation rate of colorectal cancer persister cells. Nat. Genet. 2022, 54, 976–984. https://doi.org/10.1038/s41588-022-01105-z.
  68. Sahoo, S.; Mishra, A.; Kaur, H.; et al. A mechanistic model captures the emergence and implications of non-genetic heterogeneity and reversible drug resistance in ER+ breast cancer cells. NAR Cancer 2021, 3, zcab027. https://doi.org/10.1093/narcan/zcab027.