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Drug tolerance and biomembranes.

Our understanding of the structure and function of biomembranes is now at a stage where we can begin to examine drug actions on the membrane bilayer. Cells need a certain optimal degree of fluidity in their membranes and some organisms can adapt their membrane composition to maintain the appropriate fluidity under changing environmental conditions. Chronic administration of membrane-disrupting drugs may evoke such an adaptive process, which would show itself in vivo as drug tolerance.

Adaptation, Physiological↗
PubMed1977

Drug tolerance in biomembranes: a spin label study of the effects of ethanol.

Ethanol in vitro increased the fluidity of spin-labeled membranes from normal mice. Membranes from mice that had been subjected to long-term ethanol treatment were relatively resistant to this fluidizing effect. The data suggest that the membranes themselves had adapted to the drug, a novel form of drug tolerance.

Adaptation, Physiological↗
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↗
PubMed1977

The CMF program for operable breast cancer with positive axillary nodes. Updated analysis on the disease-free interval, site of relapse and drug tolerance.

In a prospective randomized study adjuvant combination chemotherapy with CMF was administered for 12 monthly cycles to 207 patients subjected to radical mastectomy (Halsted or extended) and treatment failure was compared to that observed in 179 patients whose primary therapy consisted only of radical surgery (control group). All patients of both groups had histologically positive axillary lymph nodes. At three years from mastectomy the total failure time distribution was 45.7% in control patients compared to 26.3% in women given CMF (P less than 0.0001). New disease manifestations were higher in the subgroup with four or more nodes (64.9% vs 41.5%) compared to that with one to three nodes (37.9% vs 19.1%). Premenopausal controls showed a progressively higher incidence of treatment failure compared to CMF patients (P=0.00001). The decreased recurrence rate in postmenopausal women given CMF was appreciable only during the first 12 months. From this time on, the difference no longer existed. The cumulative percent of recurrence in patients without or with drug-induced amenorrhea (27.2% vs 9.2%) was not statistically significant. At three years 21.4% of control patients have died of progressive cancer compared to 10.4% of CMF patients. The difference in the survival curves was not significant (P=0.08). Toxicity was moderate and reversible. No drug induced neoplasm was observed. Present results confirm the efficacy of 12 CMF cycles in premenopausal patients. Postmenopausal women probably require a more intensive and prolonged adjuvant chemotherapy.

Amenorrhea↗
PubMed1975

Drug-induced tolerance: selective induction with immunosuppressive drugs and their synergistic interaction.

Drug-induced tolerance to polyinosinic-polycytidylic acid was studied in NZB/W mice. A single injection of cyclophosphamide (CY) or methotrexate (MTX) induced tolerance when given 24 h after antigen, whereas azathioprine (AZ) and methylprednisolone (MP) did not. However, MP and MTX each synergized with a nontolerogenic dose of CY. In addition, MP and AZ further reduced the tolerance induced by low but tolerogenic doses of CY. Drug combinations in the induction of tolerance may have wide application in the fields of clinical immunology and transplantation.

Ammonium Sulfate↗
PubMed1979

The interaction of thermal tolerance with drug cytotoxicity in vitro.

The effect of preheating EMT6 cells in vitro on their response to cytotoxic agents of either 43 degrees C or 37 degrees C has been investigated. Preheating for 3 h at 40 degrees C produced measurable protection (thermal tolerance) to subsequent treatment for 1 h at 43 degrees C. This preheat treatment was further found to reduce cell killing by BLM and BCNU (drug tolerance) present during 1 h at 43 degrees C. In contrast, no such heat-induced drug tolerance was seen with ADR. An additional effect with ADR was the apparent elimination of heat-induced thermal tolerance at toxic drug doses. However, preheating under these conditions had no effect on the subsequent cytotoxicity of any of these drugs at 37 degrees C. Also, preheating for 1 h at 43 degrees C was found to sensitize cells to BLM and BCNU toxicity at 37 degrees C but to protect against ADR toxicity. The results are discussed in relation to known mechanisms of cell killing by heat and of thermal tolerance.

Animals↗
PubMed1979

[Comparison of bio-availability, antianaemic efficacy, tolerance and drug costs in oral iron(II) and iron(III) preparations (author's transl)].

In addition to a clinical study which investigated the bio-availability of three oral iron preparations S, L and X by using postabsorption serum iron concentration curves, the same drugs were compared in order to study their antianaemic efficacy, tolerance and drug costs arising during and iron therapy. Moreover, these iron drugs were related to other current clinical reports. Within all three iron preparations a very good correlation was found between bio-availability and haematopoietic efficacy: The very good absorbability of the bivalent quick release stick capsule preparation S (= 100%) corresponded with a very good capacity of haemoglobin regeneration (2,6 +/- 0,4 g Hb/1/day) whereas due to a very low absorbability (10% to 16%) the antianaemic efficacy of both iron(III) preparations L and X had to be rated as moderate to predominantly poor. In normal therapeutic dosis all three iron preparations showed no differences in tolerance. The ratio of side effects was similar to that after ingestion of placebo. In comparing the drug costs during a therapy leading to a real absorption of 1 g of iron the most effective iron(II)sulfate preparation S is 3.6 to 12.6 times cheaper than the compared trivalent preparations L and X. Therefore, there is no justification for the further production or introduction on the market of trivalent iron preparations.

Absorption↗