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Review
. 2024 Aug 14;9(1):209.
doi: 10.1038/s41392-024-01891-4.

Drug tolerant persister cell plasticity in cancer: A revolutionary strategy for more effective anticancer therapies

Jun He  1   2 , Zejing Qiu  1   2 , Jingjing Fan  1   2 , Xiaohong Xie  3 , Qinsong Sheng  4 , Xinbing Sui  5   6
Affiliations
Review

Drug tolerant persister cell plasticity in cancer: A revolutionary strategy for more effective anticancer therapies

Jun He et al. Signal Transduct Target Ther. .

Abstract

Non-genetic mechanisms have recently emerged as important drivers of anticancer drug resistance. Among these, the drug tolerant persister (DTP) cell phenotype is attracting more and more attention and giving a predominant non-genetic role in cancer therapy resistance. The DTP phenotype is characterized by a quiescent or slow-cell-cycle reversible state of the cancer cell subpopulation and inert specialization to stimuli, which tolerates anticancer drug exposure to some extent through the interaction of multiple underlying mechanisms and recovering growth and proliferation after drug withdrawal, ultimately leading to treatment resistance and cancer recurrence. Therefore, targeting DTP cells is anticipated to provide new treatment opportunities for cancer patients, although our current knowledge of these DTP cells in treatment resistance remains limited. In this review, we provide a comprehensive overview of the formation characteristics and underlying drug tolerant mechanisms of DTP cells, investigate the potential drugs for DTP (including preclinical drugs, novel use for old drugs, and natural products) based on different medicine models, and discuss the necessity and feasibility of anti-DTP therapy, related application forms, and future issues that will need to be addressed to advance this emerging field towards clinical applications. Nonetheless, understanding the novel functions of DTP cells may enable us to develop new more effective anticancer therapy and improve clinical outcomes for cancer patients.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
The historical timeline of the DTP concept from the inception to the present peak. At the initial beginning, the discovery of antibiotics and the drug resistance phenomenon was the first critical period of human cognitive resistance (Stage 1). After recognizing cancer and traditional chemical therapy, the frequently limited effectiveness of treatment has led researchers to observe the widespread problem of drug resistance in anticancer drug therapy– (Stage 2). The newly developed targeted therapy also owns the problem of drug resistance in anticancer therapy,– which further deepens the thinking on the root nature of cancer drug resistance (Stage 3). With the initial observation of a chromatin-mediated reversible drug-tolerant state in the targeted therapy of non-small cell lung cancer,,, the concept of DTP has been proposed and its possibility has been preliminarily verified (Stage 4). Since then, more and more researchers have used the concept of DTP cell to bring several studies on its mechanism,,,,,,,,,,,– and treatment related,,,,,,,, analysis, and a variety of different mechanisms and possible solutions have filled the entire field of DTP cells research, and a spurt of development stage constitutes the present new period (Stage 5)
Fig. 2
Fig. 2
There are two primary hypotheses regarding the origin or transformation mechanisms of DTP cells and resistance to anticancer drugs: primary and secondary. Clonal Selection Mechanism (Part a): In the hypothesis of clonal selection, primary drug resistant cells with natural gene mutations, receptor/ligand changes, and effector abnormality are present within normal cancer cells and lead to cancer recurrence during external anticancer drug therapy. Drug-induction Mechanism (Part b): In the hypothesis of drug induction, the initial drug insensitive cells result from the inducing effect of anticancer drug, and lead to characteristic DTP cells during long-term drug maintenance and eventually reactivation and proliferation. Regardless of the hypothesis’s origin, DTP cells ultimately resist drug-directed cancer recurrence. (Drawn by figdraw)
Fig. 3
Fig. 3
Notable characteristics of DTP cell transformation. Cycle Restriction (a): DTP cells concentrate in the G1 phase and do not undergo further proliferation. Embryonic-like Torpor/Diapause (b): Similar to organisms entering an embryonic-like state in response to external stimulus, DTP cells also exhibit a torpor/diapause state when stimulated by drugs in cancer cells. Stem-like Phenotype (Part c): DTP cells express some stemness markers as known cancer stem cells, such as CD133/CD166/ALDH, and have cellular plasticity. State Reversibility (d): DTP cells produced by cancer cell undergoing anticancer therapy can revert to a repopulating cancer cell state after discontinuation of drug therapy for a certain duration of time and subsequently exhibit DTP cells upon resuming treatment. (Drawn by figdraw)
Fig. 4
Fig. 4
Multi-mechanisms analysis of DTP resistance. Molecular Modification (a): DTP cells exhibit a significant number of molecular modifications as compared to parental tumor cells, encompassing DNA methylation, acetylation, phosphorylation, and histone modification. Signaling Pathways (b): Signaling plays a crucial role in cancer cells, and altered pathways in DTP cells contribute to transcription regulation, DTP formation, and drug resistance progress. Tumor Micro-environment (c): TME surrounding the DTP cells changes to accommodate both drug action and the environment’s alterations. Metabolic Reprogramming (d): DTP cells rely more on mitochondrial respiration than most cancer cells that survive using glycolysis, for their energy needs. Redox Balance (e): The robust redox system within DTP cells enables them to withstand the balance between oxidative eustress and distress. These multi-mechanisms interact with each other and together provide the stable basis for drug resistance in DTP cells. (Drawn by figdraw)
Fig. 5
Fig. 5
As shown above, DTP cells undergo numerous modifications to genes and signaling pathways. Important modifications include KDM5A-mediated DNA methylation modification, increased expression of GAS6/AXL, adjustments to EGFR, JAK/STAT3 and their downstream pathway, activation of the Hippo pathway and its YAP/TEAD branch, the Notch pathway, the Wnt/β-catenin pathway, and modulation of E-cadherin. Ultimately, the drug resistance of DTP cells has been affected. (Drawn by figdraw)
Fig. 6
Fig. 6
Redox regulation in DTP cells. The Redox System Balance (a/b) is influenced by mitochondrial respiratory metabolism, anticancer therapeutic drug effects, radiotherapy, inflammatory stimulation, and external oxidative stress. These factors elevate the ROS level of DTP cells (Pro-Oxidation Part). Then DTP meets these oxidative stimuli by multiple reductive protection mechanisms with redox compensation like GSH/NADPH/HK2 through enhancing the expression of GPX4 and ALDH, and other potential related elements (Pro-Reduction Part). The balance between the two ensures the redox stability of DTP cells. Other potential redox mechanism (c): external drug stimuli, particularly BH3-mimetics can trigger an incomplete mitochondrial outer membrane permeabilization (iMOMP) in DTP cells by acting on Bcl-2 family anti-apoptotic proteins (including BAX, BAK, BOK, etc.) and reducing caspase activation. Drug treatment protects DTP cells from apoptosis by inhibiting membrane permeabilization and caspase activation. Additionally, a protective mechanism against oxidative stress in DTP is stimulated by the drug, which acts on the cytochromeC-HRI-eIF2a-ISR/ATF4 axis. (Drawn by figdraw)
Fig. 7
Fig. 7
Selected Anti-DTP drugs. a: Preclinical drugs; b: Novel use for old drugs; c: Natural products. (Drawn by chemdraw)
Fig. 8
Fig. 8
Anticancer Therapy Long-Term View. Past known axis (a) focuses on the drug resistance progress of minimal residual disease (MRD) after anticancer therapy and pursues to prevent the generation of MRD which leads to cancer recurrence. However, the emergence of a new possible axis (b) acknowledges the presence of DTP cells and reactivated one as the fundamental condition. Consequently, two new therapeutic schemes are proposed to simultaneously inhibit and eliminate DTP, thereby aiming for better long-term therapeutic results. (Drawn by figdraw)
Fig. 9
Fig. 9
DTP Burden Forecast Trends. Periodic Eliminating therapy (a) involves administering drugs to DTP cells regularly to diminish the DTP burden before it surpasses the proliferation baseline, therefore ensuring it remains below this threshold. On the other hand, continuous inhibitory therapy (b) is focused on impeding the buildup of the DTP burden and ultimately steadying the quantity of DTP cells at a plateau that is beneath the proliferative baseline
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