Targeting drug-tolerant cells: A promising strategy for overcoming acquired drug resistance in cancer cells

Abstract

Drug resistance remains the greatest challenge in improving outcomes for cancer patients who receive chemotherapy and targeted therapy. Surmounting evidence suggests that a subpopulation of cancer cells could escape intense selective drug treatment by entering a drug-tolerant state without genetic variations. These drug-tolerant cells (DTCs) are characterized with a slow proliferation rate and a reversible phenotype. They reside in the tumor region and may serve as a reservoir for resistant phenotypes. The survival of DTCs is regulated by epigenetic modifications, transcriptional regulation, mRNA translation remodeling, metabolic changes, antiapoptosis, interactions with the tumor microenvironment, and activation of signaling pathways. Thus, targeting the regulators of DTCs opens a new avenue for the treatment of therapy-resistant tumors. In this review, we first provide an overview of common characteristics of DTCs and the regulating networks in DTCs development. We also discuss the potential therapeutic opportunities to target DTCs. Last, we discuss the current challenges and prospects of the DTC-targeting approach to overcome acquired drug resistance. Reviewing the latest developments in DTC research could be essential in discovering of methods to eliminate DTCs, which may represent a novel therapeutic strategy for preventing drug resistance in the future.

Keywords: acquired drug resistance; drug‐tolerant cells; phenotype plasticity; translational remodeling.

FIGURE 1

Cancer cells can acquire drug resistance via genetic and nongenetic adaptation mechanisms. (A) A small number of subclones have preexisting or develop new genetic alterations that confer drug resistance, and these drug‐resistant tumor cells survive during the treatment, leading to drug resistance. (B) There are two hypotheses for the source of DTCs and acquisition of tumor resistance. The first (top) is that a subpopulation of cancer cells with DTC characteristics presents in treatment‐naive tumors and it selectively survive from drug exposure (clonal selection); and the second (bottom) is that drug treatment induces a phenotypic transition of tumor cells into the DTCs. DTCs exhibit a reversible phenotype; they can resume proliferation and resensitize their drug sensitivity after termination of drug treatment, and they eventually acquire drug resistance through multiple mechanisms under continuous treatment. DTC, drug‐tolerant cell.

FIGURE 2

Conceptual similarities of tolerance in bacteria and tumor cell. (A) The survival curve describes the changes in bacterial status when exposed to antibiotics. Sensitive bacteria (cyan) are completely eliminated with antibiotic treatment, while antibiotic‐resistant bacteria (red) continue to proliferate. Antibiotic‐tolerant bacteria can survive when exposed to antibiotics and quickly reproduce after the removal of antibiotics, regaining sensitivity to antibiotics (purple). (B) The survival curve depicts the emergence of drug‐tolerant cells (DTCs) in tumors following chemotherapy or targeted therapy, as well as their reversible characteristics. The hallmark of the tolerant state is its reversibility upon discontinuation of the drug, indicating the absence of resistance‐related mutations.

FIGURE 3

The biological characteristics of DTCs. The features of DTC including reversible drug sensitivity and reservoir of multiple resistant mutations (A), slow cycling (B), and phenotype plasticity (CSC‐like, EMT‐like, senescence‐like and diapause‐like changes) (C). CSC, cancer stem cells; EMT, epithelial–mesenchymal transition; DTC, drug‐tolerant cell.

FIGURE 4

The molecular mechanisms associated with DTCs. The regulation mechanisms of the DT state: (1) Epigenomic, transcriptional and translational regulation: DTCs usually display upregulation of demethylases such as KDM5 and KDM6, which reduces histone H3K4me and H3K27me. In addition, transcriptional and translational regulation is observed in DTCs; (2) metabolic changes: DTCs are dependent on mitochondrial respiration for their energy production. Fatty acid β‐oxidation and autophagy contribute to this energy production. DTCs have an antioxidant stress capacity via upregulation of GPX4, ALDH, and NCP1L1 to protect them against the oxidative stress‐induced cytotoxicity; (3) signaling pathway: activating alternative and bypass pathways, such as IGF‐1R, AXL,FGFR3, and HER3 pathways, play an important role in DTC survival; and (4) antiapoptosis and tumor TME: DTCs have the ability to resist drug‐induced apoptosis via upregulation of SLUG and MCL‐1 and drug treatment affects microenvironmental nontumor cells such as CAFs to promote DTC formation. CAF, cancer‐associated fibroblast; DTC, drug‐tolerant cell; EMT, epithelial–mesenchymal transition; FGFR, fibroblast growth factor receptor; HER3, human epidermal growth factor receptor 3; IGF‐1R, insulin‐like growth factor 1 receptor; TME, tumor microenvironment.

FIGURE 5

Challenges of the DTC‐targeting approach to overcome acquired drug resistance. (A) Origin of DTC (Darwinian selection or Lamarkian induction). (B) Tolerance of tumor cell to chemotherapy or targeted therapy has been confirmed, while tolerance to immunotherapy remains unclear. (C) Intra‐ and intertumor DTC heterogeneity may exist. (D) The present models used for DTC include 2D culture, 3D culture, organoids and PDX models. DTC, drug‐tolerant cell; PDX, patient‐derived xenografts.