# Drug-tolerant persister cells

Source: https://onco.cc/pathways/drug-tolerant-persisters/  
OnCo record `drug-tolerant-persisters` (Pathway). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Even when a drug wipes out 99% of a tumour, a few cells survive without any resistance mutation: they go quiet, stop dividing, and wait. These persisters are the seed of relapse. They are hard to kill precisely because they are not doing much, but they have their own weaknesses.

## Summary

First described by Sharma et al. (2010) in EGFR-mutant lung cancer cells surviving erlotinib, persisters are a reversible, largely non-genetic state resembling bacterial persistence and embryonic diapause: slow-cycling, with chromatin changes (KDM5A-dependent histone demethylation, H3K27me3 gain), activation of IGF1R, YAP/TAZ, NF-κB, Notch and AXL, autophagy, altered metabolism (reliance on fatty acid oxidation, low glutathione), reduced apoptotic priming, upregulated ABC transporters, and a mesenchymal-like, ALDH-high phenotype. Their lipid metabolism creates dependence on GPX4, so ferroptosis inducers kill them selectively in models. During persistence, downregulated repair and APOBEC activity increase mutagenesis, so genuine resistance mutations (EGFR T790M, C797S) often arise from persisters ('bet hedging' then 'commitment'). MRD detected by ctDNA after targeted therapy or in adjuvant settings partly reflects this population; senescence-like persisters share SASP features. Strategies: drug holidays and intermittent dosing to prevent commitment, GPX4/ferroptosis inducers, BCL-XL/MCL-1 inhibitors to remove the survival buffer, KDM5 or EZH2 inhibitors to block the epigenetic switch, and upfront combinations that hit the persister programme (osimertinib + chemotherapy in FLAURA2, + amivantamab in MARIPOSA).

## Fields

- Kind: Pathway
- Last checked: 2026-09-09
- Tags: mechanism; mechanics-atlas
- Analogy: Bears in hibernation while the forest burns. Poison meant for grazing animals does nothing to a sleeping bear; but a hibernating bear cannot run, so a hunter who knows where the den is (GPX4, BCL-XL) can strike.
- Interventions: Upfront combinations that pre-empt persisters: osimertinib + chemotherapy (FLAURA2), amivantamab + lazertinib (MARIPOSA), BRAF + MEK + anti-PD-1; GPX4 and ferroptosis inducers, BCL-XL/MCL-1 inhibitors, KDM5 and EZH2 inhibitors (preclinical to phase 1); MRD-guided treatment: ctDNA clearance to de-escalate, persistence to intensify or switch; Intermittent or adaptive dosing to delay commitment to resistance (trials in melanoma and prostate cancer)

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Persister_cell
- Sharma et al., A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations (Cell 2010): https://doi.org/10.1016/j.cell.2010.02.027
- Shen, Vagner & Robert, Persistent cancer cells: the deadly survivors (Cell 2020): https://doi.org/10.1016/j.cell.2020.10.027

## Connected records

- technologies: [Continuous and near-continuous ctDNA monitoring](https://onco.cc/technologies/continuous-ctdna-monitoring/), [Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET)](https://onco.cc/technologies/epigenetic-drugs/), [MRD / molecular residual disease testing](https://onco.cc/technologies/mrd-testing/), [Senolytics and senescence-directed therapy](https://onco.cc/technologies/senescence-targeting/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/)
- targets: [BCL-2](https://onco.cc/targets/bcl2/), [BRAF](https://onco.cc/targets/braf/), [EGFR](https://onco.cc/targets/egfr/), [EZH2](https://onco.cc/targets/ezh2/), [KDM5A](https://onco.cc/targets/kdm5a/), [KRAS](https://onco.cc/targets/kras/)
- drugs: [Amivantamab](https://onco.cc/drugs/amivantamab/), [Lazertinib](https://onco.cc/drugs/lazertinib/), [Osimertinib](https://onco.cc/drugs/osimertinib/), [Signatera](https://onco.cc/drugs/signatera/), [Venetoclax](https://onco.cc/drugs/venetoclax/)
- pathways: [Autophagy](https://onco.cc/pathways/autophagy/), [Cancer stem cells & phenotypic plasticity](https://onco.cc/pathways/cancer-stem-cells-plasticity/), [Cellular senescence](https://onco.cc/pathways/senescence/), [Clonal evolution & minimal residual disease](https://onco.cc/pathways/clonal-evolution/), [Epigenetic reprogramming](https://onco.cc/pathways/epigenetic-reprogramming/), [Ferroptosis & regulated cell death](https://onco.cc/pathways/ferroptosis-cell-death/), [Resistance routes: how a blocked pathway comes back](https://onco.cc/pathways/resistance-routes-map/)
- terms: [Cancer stem cell theory and phenotypic plasticity](https://onco.cc/terms/cancer-stem-cell-theory/), [Circulating tumour DNA (ctDNA)](https://onco.cc/terms/ctdna/), [Clonal evolution and the ecological view of cancer](https://onco.cc/terms/clonal-evolution-theory/), [Drug resistance (primary and acquired)](https://onco.cc/terms/resistance/), [EGFR C797S](https://onco.cc/terms/c797s/), [Epigenetic progenitor theory: cancer without a first mutation](https://onco.cc/terms/epigenetic-progenitor-theory/), [Hallmark (2022): non-mutational epigenetic reprogramming](https://onco.cc/terms/nonmutational-epigenetic-reprogramming/), [Minimal / molecular residual disease (MRD)](https://onco.cc/terms/mrd/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [Dormant cells and minimal residual disease](https://onco.cc/bottlenecks/b-dormancy-mrd/)
- key papers: [A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations](https://onco.cc/key-papers/paper-sharma-cell/), [Assessment of resistance mechanisms and clinical implications in patients with EGFR T790M-positive lung cancer and acquired resistance to osimertinib](https://onco.cc/key-papers/paper-oxnard-osimertinib-resistance-mechanisms-jama-oncol-2018/), [Persistent Cancer Cells: The Deadly Survivors](https://onco.cc/key-papers/paper-shen-cell/)
- cancers: [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)

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