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Results for “Drug-tolerant persister”

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6 recordsLinked to original sources
PubMed2026

Transcriptomic and network analyses identify epigenetic regulators of drug-tolerant persister (DTP) subsets in EGFR-mutant HCC827 non-small cell lung cancer.

BACKGROUND: The clinical efficacy of osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), in EGFR-mutant non-small cell lung cancer (NSCLC) is limited by the inevitable acquired resistance. Drug-tolerant persister (DTP) cells, which survive initial therapy, are considered a key reservoir for this resistance. Understanding the molecular characteristics of DTPs is essential for developing strategies to prevent relapse. OBJECTIVE: This study aimed to characterize the transcriptomic landscape of osimertinib-tolerant DTP cells and identify key epigenetic regulators associated with the DTP phenotype in EGFR-mutant HCC827 NSCLC cells through integrated transcriptomic and network analyses. METHODS: We established an in vitro model of osimertinib tolerance using an EGFR-mutant (exon 19 deletion) HCC827 NSCLC cell line. Parental HCC827 cells and DTP subsets were subjected to transcriptomic analysis by RNA sequencing (RNA-seq). Differentially expressed genes were identified, followed by bioinformatics analyses, including Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and protein-protein interaction (PPI) network analyses to identify key biological processes driving the DTP phenotype. Key findings were validated using quantitative real-time PCR (qPCR). RESULTS: Osimertinib treatment induced a morphologically distinct DTP population. Transcriptomic profiling revealed a marked shift in gene expression compared to parental cells. Functional enrichment analysis showed significant upregulation of epigenetic pathways. PPI network analysis identified a core module of eight hub genes, including histone deacetylases (HDAC5, HDAC9), sirtuins (SIRT1, SIRT2), and histone acetyltransferase (KAT2B). qPCR confirmed increased expression of HDAC5, HDAC9, and SIRT1. CONCLUSION: Epigenetic reprogramming accompanies the transition to an osimertinib-tolerant state in EGFR-mutant HCC827 cells. Targeting HDACs and sirtuins may represent a promising strategy to eliminate DTP subpopulations and delay or prevent acquired resistance.

Drug-tolerant persister↗
PubMed2022

Ontogeny and Vulnerabilities of Drug-Tolerant Persisters in HER2+ Breast Cancer.

UNLABELLED: Resistance to targeted therapies is an important clinical problem in HER2-positive (HER2+) breast cancer. "Drug-tolerant persisters" (DTP), a subpopulation of cancer cells that survive via reversible, nongenetic mechanisms, are implicated in resistance to tyrosine kinase inhibitors (TKI) in other malignancies, but DTPs following HER2 TKI exposure have not been well characterized. We found that HER2 TKIs evoke DTPs with a luminal-like or a mesenchymal-like transcriptome. Lentiviral barcoding/single-cell RNA sequencing reveals that HER2+ breast cancer cells cycle stochastically through a "pre-DTP" state, characterized by a G0-like expression signature and enriched for diapause and/or senescence genes. Trajectory analysis/cell sorting shows that pre-DTPs preferentially yield DTPs upon HER2 TKI exposure. Cells with similar transcriptomes are present in HER2+ breast tumors and are associated with poor TKI response. Finally, biochemical experiments indicate that luminal-like DTPs survive via estrogen receptor-dependent induction of SGK3, leading to rewiring of the PI3K/AKT/mTORC1 pathway to enable AKT-independent mTORC1 activation. SIGNIFICANCE: DTPs are implicated in resistance to anticancer therapies, but their ontogeny and vulnerabilities remain unclear. We find that HER2 TKI-DTPs emerge from stochastically arising primed cells ("pre-DTPs") that engage either of two distinct transcriptional programs upon TKI exposure. Our results provide new insights into DTP ontogeny and potential therapeutic vulnerabilities. This article is highlighted in the In This Issue feature, p. 873.

Breast Neoplasms↗
PubMed2026

Epigenetic Repression of TP53 Transcription Underlies Cancer Cell Persistence for Carboplatin Resistance in Non-Small Cell Lung Cancer.

While chemoresistance in non-small cell lung cancer (NSCLC) cells has historically been attributed to permanent genetic mutations, emerging evidence highlights the role of nongenetic transcriptional plasticity and 'drug-tolerant persister' cells. To systematically map these epigenetic vulnerabilities, we utilized a genome-wide CRISPR interference library to screen wild-type TP53 NSCLC (A549) cells under carboplatin selection. Using the DrugZ algorithm and subsequent pathway enrichment analyses, this screen revealed that transcriptional suppression of interstrand crosslink DNA repair networks, including the Fanconi anemia pathway, markedly sensitized cells to carboplatin. Unexpectedly, transcriptional silencing of TP53 and its downstream target CDKN1A emerged as the strongest drivers of resistance, enabling cells to bypass therapy-induced senescence and maintain their proliferative potential later. To validate these findings in a clinically relevant context, we established a chronic carboplatin-resistant cell model (A549CarboR cells). A549CarboR exhibited a reduction in TP53 transcripts, along with decreased H3K27 acetylation and increased DNA hypermethylation on its promoter. Epigenetic remodeling using the DNA methyltransferase inhibitor (DNMTi) was associated with unblocking TP53 transcription, restored p53 signaling, and resensitization of resistant cells to carboplatin. Conversely, histone deacetylase inhibitors induced CDKN1A transcription to bypass TP53, indicating distinct epigenetic circuits. Collectively, the results demonstrate for the first time that TP53 expression is dynamically regulated at the transcriptional level through promoter methylation related to the drug tolerance. These insights emphasize that epigenetic silencing, rather than exclusive genetic loss-of-function, contribute to platinum resistance and underscore the therapeutic potential of pairing platinum regimens with DNMTi to target the transcriptomic plasticity of persistent cancer cell populations.

CRISPR interference screening↗
PubMed2026

Targeting EGFR-Mutant Non-Small Cell Lung Cancer in Asia: An Update on Monotherapy and Combination Therapy With EGFR Inhibitors.

EGFR-mutant lung cancer represents a major subtype of non-small cell lung cancer in Asia, with particularly high prevalence in never-smokers, women, and patients with adenocarcinoma histology. Although this clinicopathologic enrichment has been recognized for more than two decades, the mechanisms underlying the excess frequency of EGFR-mutant disease in Asian populations remain only partially understood. Accumulating evidence suggests a multifactorial basis involving host genetic susceptibility and diversity, endogenous mutational processes and exogenous exposures such as ambient particulate matter. In particular, recent genomic and experimental studies support a tumour-promotion framework in which inflammatory microenvironmental cues may facilitate the outgrowth of pre-existing oncogenic clones, while mutational signatures provide genomic footprints of these processes. In parallel, the treatment landscape for EGFR-mutant non-small cell lung cancer has evolved substantially with successive generations of EGFR tyrosine kinase inhibitors (EGFR-TKIs), leading to marked improvements in survival. However, acquired resistance remains inevitable in most patients with advanced disease and is driven by both genetic and non-genetic mechanisms, including secondary EGFR alterations, bypass pathway activation, TP53-associated genomic instability, adaptive mutagenesis, and drug-tolerant persister states. These insights have provided a strong rationale for combination strategies beyond EGFR-TKI monotherapy. In this review, we summarize current understanding of the epidemiology and biological basis of EGFR-mutant lung cancer in Asia and discuss the preclinical rationale and emerging clinical evidence supporting combination approaches with chemotherapy, anti-angiogenic agents, and EGFR/MET-directed therapies.

EGFR mutations↗
PubMed2025

Integrating multiscale mathematical modeling and multidimensional data reveals the effects of epigenetic instability on acquired drug resistance in cancer.

Biological and dynamic mechanisms by which Drug-tolerant persister (DTP) cells contribute to the development of acquired drug resistance have not been fully elucidated. Here, by integrating multidimensional data from drug-treated PC9 cells, we developed a novel multiscale mathematical model from an evolutionary perspective that encompasses epigenetic and cellular population dynamics. By coupling stochastic simulation with quantitative analysis, we identified epigenetic instability as the most prominent kinetic feature related to the emergence of DTP cell subpopulations and the effectiveness of intermittent treatment. Moreover, we revealed the optimal schedule for intermittent treatment, including the optimal area for therapeutic time and drug holidays. By leveraging single-cell RNA-seq data characterizing the drug tolerance of lung cancer, we validated the predictions made by our model and further revealed previously unrecognized biological features of DTP cells, such as cell autophagy and migration, as well as new biomarker genes of therapeutic tolerance. Our work not only provides a paradigm for the integration of multiscale mathematical models with newly emerging genomics data but also improves our understanding of the crucial roles of DTP cells and offers guidance for developing new intermittent treatment strategies against acquired drug resistance in cancer.

Drug Resistance, Neoplasm↗
PubMed2025

The cGAS-STING pathway is a master regulator of OCT4 expression in persistent sarcoma cells and enhances cellular immunotherapy with NK and CIK lymphocytes.

Advanced sarcomas have a poor prognosis and limited therapeutic options. Disease recurrence is caused by persistent cells that survive drug treatments. The alkylating agent trabectedin, when combined with the poly (ADP-ribose) polymerase 1 (PARP1) inhibitor olaparib, exhibits variable antitumor effects in advanced sarcomas. In this study, we demonstrate that the expression of the transcription factor OCT4 is upregulated in persistent cells that survive treatment with trabectedin and olaparib, through the cGAS-STING-IRF3-IFNβ pathway. This route also leads to the upregulation of natural killer (NK) and cytokine-induced killer (CIK) lymphocyte activating ligands. These molecular events enhance the antitumor efficacy of immunotherapy with NK and CIK cells, targeting both the bulk population and residual drug-tolerant cells. In conclusion, the activation of the cGAS-STING pathway has a double-edged effect, enriching the OCT4+ persistent cell population while increasing the expression of NK/CIK ligands. The addition of olaparib to trabectedin potentiates the cGAS-STING pathway activation and the upregulation of NKG2DLs, while simultaneously counteracting the OCT4 overexpression. Therefore, sequential treatment with trabectedin and olaparib followed by NK/CIK immunotherapy represents a promising strategy against advanced sarcomas and warrants further investigation.

Humans↗