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Cited by 111Cancer Cells and MetastasisCell death mechanisms and regulationMathematical Biology Tumor Growth

Fighting Drug Resistance through the Targeting of Drug-Tolerant Persister Cells

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De Conti, Giulia, Dias, Matheus Henrique, Bernards, René·2021·Cancers
DOI 10.3390/cancers13051118PMC PMC7961328
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Abstract

Designing specific therapies for drug-resistant cancers is arguably the ultimate challenge in cancer therapy. While much emphasis has been put on the study of genetic alterations that give rise to drug resistance, much less is known about the non-genetic adaptation mechanisms that operate during the early stages of drug resistance development. Drug-tolerant persister cells have been suggested to be key players in this process. These cells are thought to have undergone non-genetic adaptations that enable survival in the presence of a drug, from which full-blown resistant cells may emerge. Such initial adaptations often involve engagement of stress response programs to maintain cancer cell viability. In this review, we discuss the nature of drug-tolerant cancer phenotypes, as well as the non-genetic adaptations involved. We also discuss how malignant cells employ homeostatic stress response pathways to mitigate the intrinsic costs of such adaptations. Lastly, we discuss which vulnerabilities are introduced by these adaptations and how these might be exploited therapeutically.

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  • Drug-Tolerant Persister (DTP) cells can derive from pre-treatment stochastic expression variability in cell populations, or from treatment-induced changes in transcriptional profiles or epigenetic markers.

    “Drug-Tolerant Persister (DTP) cells can derive from pre-treatment stochastic expression variability in cell populations, or from treatment-induced changes in transcriptional profiles or epigenetic markers [115,117,118].”

    From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [118]

    Section 2.5 (Cellular Plasticity; page not available) describes treatment-associated changes in DTP transcriptional programs and chromatin organization. The Introduction says a persister population may pre-exist treatment, but only conditionally; it does not attribute that pre-existence to stochastic expression variability. That proposed origin is not supported by this copy. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Cancer cells use non-mutational adaptations to resist a wide variety of single drugs or drug combinations, including inhibitors targeting BRAF, MEK, EGFR, and KRAS.

    “Cancer cells use non-mutational adaptations to resist a wide variety of single drugs or drug combinations, including inhibitors targeting BRAF, MEK, EGFR, and KRAS [118,119].”

    From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [118]

    The Introduction describes non-genetic drug tolerance after EGFR and BRAF inhibition, while the Cellular Plasticity section describes adaptation during MEK-inhibitor treatment. The paper does not establish resistance through non-mutational adaptation to KRAS inhibitors; its mention of oncogenic KRAS concerns KRAS ablation, not inhibition by a drug. It also does not establish the claimed breadth across drug combinations. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • In the early stages of treatment, non-mutational DTP cell lines can enter a quiescent non-growth state.

    “In the early stages of treatment, non-mutational DTP cell lines can enter a quiescent non-growth state [115,118,120].”

    From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [118]

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Cited by

Sorted by citations

Authors
De Conti, G., Dias, M. H., & Bernards, R.
Affiliations
  • Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
  • The Netherlands Cancer Institute (NL)
Corresponding author
Bernards, René
ORCID
Venue
Cancers
Publisher
MDPI AG
Published
2021-03-05
Volume
13
Issue
5
Pages
1118
ISSN
2072-6694 (ISSN-L)
DOI
10.3390/cancers13051118
PMC
PMC7961328
OpenAlex
W3134602318
Cited by
111
References
12
Citations by year
2026: 14 · 2025: 19 · 2024: 34 · 2023: 19 · 2022: 19 · 2021: 6
FWCI
2.45
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancers (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
ERC advanced grant (SENCAN, #787925)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Physical Sciences › Mathematics › Modeling and Simulation › Mathematical Biology Tumor Growth
Keywords
drug resistance, drug-tolerant persister cells, cancer stemness, stress response pathways, therapeutic vulnerabilities, cancer therapy

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