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Exploiting evolutionary steering to induce collateral drug sensitivity in cancer.

ABSTRACT: Drug resistance mediated by clonal evolution is arguably the biggest problem in cancer therapy today. However, evolving resistance to one drug may come at a cost of decreased fecundity or increased sensitivity to another drug. These evolutionary trade-offs can be exploited using 'evolutionary steering' to control the tumour population and delay resistance. However, recapitulating cancer evolutionary dynamics experimentally remains challenging. Here, we present an approach for evolutionary steering based on a combination of single-cell barcoding, large populations of 10⁸-10⁹ cells grown without re-plating, longitudinal non-destructive monitoring of cancer clones, and mathematical modelling of tumour evolution. We demonstrate evolutionary steering in a lung cancer model, showing that it shifts the clonal composition of the tumour in our favour, leading to collateral sensitivity and proliferative costs. Genomic profiling revealed some of the mechanisms that drive evolved sensitivity. This approach allows modelling evolutionary steering strategies that can potentially control treatment resistance.

SUBMITTER: Acar A

PROVIDER: S-EPMC7174377 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Exploiting evolutionary steering to induce collateral drug sensitivity in cancer

Project description:This study contains single cell RNA-seq of the non-small cell lung cancer line HCC827 in three conditions. Firstly we have sequenced the RNA of single cells of a culture of HCC827 cells grown in normal conditions (POT). In our study we then evolved two arms of the cell line, one in the presence of the drug gefitinib (40nM, G1) and the other in the presence of trametinib (100nM, T4) in HYPERflasks to avoid replating. These data were analysed using cellRanger using GRCh38. Output from cellRanger was filtered for a minimum number of detected genes and UMIs. Mitochondrial reads were excluded from analysis (Acar_2020_single_cell_raw_data.txt). The data was then imported and scaled using the package Seurat. Scaled data was then filtered for low expression of housekeeping genes. Additionally genes expressed in fewer than 20 cells were excluded from analysis. Data was then renormalised using linear normalisation and scaling on the filtered raw data (Acar_2020_single_cell_processed_data.txt). Principal component analysis was run on variable genes identified using Seurat and the top 44 component were used as input for t-SNE analysis. Clusters were then identified using FindClusters in Seurat (Acar_2020_single_cell_metadata.txt). For a full description see the associated publication.

2020-08-18 | E-MTAB-8809 | biostudies-arrayexpress

Exploiting evolutionary steering to induce collateral drug sensitivity in cancer

Project description:Exploiting evolutionary steering to induce collateral drug sensitivity in cancer

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Exploiting Temporal Collateral Sensitivity in Tumor Clonal Evolution

Project description:In this study, using a murine model of Ph+ acute lymphoblastic leukemia (Ph+ ALL), a combined pharmacological profile and drug selection experimental approach identified distinct stages of tumor clonal evolution with vulnerabilities to sets of small molecules. Through genotypic, phenotypic, signaling, and binding measurements, we identified the mutation V299L in the ABL1 kinase domain as mediator for an on-target ABL1 inhibition and hence the sensitization phenotype. To further rule out any off-target effects, we performed RNA-seq analysis of select derived cell lines. Variant calls suggest that although there were other mutations, the only mutation shared among cell lines with the sensitization phenotype and that went from 0% to 100% variant allele frequency was c.895G>C, leading to BCR-ABL1 V299L. In addition, transcriptional profile does not suggest functional changes in BCR-ABL1 V299L and WT cell lines. RNA-seq of parental murine Ph+ acute lymphoblastic leukemia (Ph+ ALL) cell line and derived cell lines (via dose escalating concentrations of dasatinib or DMSO vehicle control).

2016-04-05 | E-GEOD-72910 | biostudies-arrayexpress

Exploiting Temporal Collateral Sensitivity in Tumor Clonal Evolution

2016-04-05 | GSE72910 | GEO

Exploiting evolutionary steering in cancer therapy

Project description:Drug resistance, mediated by intra-tumour heterogeneity and clonal evolution, is arguably the biggest problem in cancer therapy today. However, evolving resistance to one drug may come at the cost of increased sensitivity to another due to so-called evolutionary trade-offs. This weakness can be exploited in the clinic using an approach called ‘evolutionary herding’ that aims at controlling the tumour cell population to delay or prevent resistance. However, model systems able to recapitulate cancer evolution experimentally are lacking and current in vitro techniques based on small populations, re-plating and escalating dose, are unsuitable to develop evolutionary herding strategies. We present a novel methodology for evolutionary herding in vitro and ex vivo using patient-derived organoids. Our approach is based on a combination of single-cell barcoding, very large populations of 108-109 cells grown without re-plating, realistic high drug doses, time-course monitoring of cancer clones, and mathematical modelling of tumour evolutionary dynamics. We demonstrate evolutionary herding in non-small cell lung cancer in vitro and in patient-derived colorectal cancer organoids (PDO). We show that herding causes controlled evolutionary bottlenecks that lead to collateral sensitivity. Through genomic analysis, we were also able to determine the mechanisms that drive such sensitivity. Our approach allows modelling evolutionary trade-offs experimentally to test patient-specific evolutionary herding strategies that can be translated into the clinic to control treatment resistance.

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Exploiting Temporal Collateral Sensitivity in Tumor Clonal Evolution.

Project description:The prevailing approach to addressing secondary drug resistance in cancer focuses on treating the resistance mechanisms at relapse. However, the dynamic nature of clonal evolution, along with potential fitness costs and cost compensations, may present exploitable vulnerabilities-a notion that we term "temporal collateral sensitivity." Using a combined pharmacological screen and drug resistance selection approach in a murine model of Ph(+) acute lymphoblastic leukemia, we indeed find that temporal and/or persistent collateral sensitivity to non-classical BCR-ABL1 drugs arises in emergent tumor subpopulations during the evolution of resistance toward initial treatment with BCR-ABL1-targeted inhibitors. We determined the sensitization mechanism via genotypic, phenotypic, signaling, and binding measurements in combination with computational models and demonstrated significant overall survival extension in mice. Additional stochastic mathematical models and small-molecule screens extended our insights, indicating the value of focusing on evolutionary trajectories and pharmacological profiles to identify new strategies to treat dynamic tumor vulnerabilities.

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Exploiting AR-Regulated Drug Transport to Induce Sensitivity to the Survivin Inhibitor YM155.

Project description:Androgen receptor (AR) signaling is fundamental to prostate cancer and is the dominant therapeutic target in metastatic disease. However, stringent androgen deprivation therapy regimens decrease quality of life and have been largely unsuccessful in curtailing mortality. Recent clinical and preclinical studies have taken advantage of the dichotomous ability of AR signaling to elicit growth-suppressive and differentiating effects by administering hyperphysiologic levels of testosterone. In this study, high-throughput drug screening identified a potent synergy between high-androgen therapy and YM155, a transcriptional inhibitor of survivin (BIRC5). This interaction was mediated by the direct transcriptional upregulation of the YM155 transporter SLC35F2 by the AR. Androgen-mediated YM155-induced cell death was completely blocked by the overexpression of multidrug resistance transporter ABCB1. SLC35F2 expression was significantly correlated with intratumor androgen levels in four distinct patient-derived xenograft models, and with AR activity score in a large gene expression dataset of castration-resistant metastases. A subset of tumors had significantly elevated SLC35F2 expression and, therefore, may identify patients who are highly responsive to YM155 treatment. IMPLICATIONS:The combination of androgen therapy with YM155 represents a novel drug synergy, and SLC35F2 may serve as a clinical biomarker of response to YM155.

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Evolutionary collateral sensitivity to pleuromutilins in vancomycin-resistant Enterococcus faecium

Project description:The rise of antibiotic resistance and decline of antibiotic discovery urgently calls for novel mechanistic understanding of pharmacological and evolutionary interactions between antibiotics and multidrug resistant bacteria to revitalize existing antibiotics. The evolutionary cross-resistance to antibiotics has received intensive attention previously. Nevertheless, whether and how bacteria develop negative responses, under the selective pressure of antibiotics by inverting the evolutionary trajectory remains unclear. Here we found an instance of collateral sensitivity, in which clinical vancomycin-resistant Enterococcus faecium (VREfm) pathogens exhibit dramatic and specific susceptibility to pleuromutilin antibiotics, decreased minimal inhibitory concentrations (MICs) from 128 µg/mL to 0.03 µg/mL. The unique trade-off between vancomycin and pleuromutilins is mediated by the epistasis between the van gene cluster and msrC encoding an ABC-F protein protecting bacterial ribosomes. We validated the efficacy of pleuromutilins in vivo through reducing colonization and promoting microbiota restoration. Our findings provide an alternative approach to inverting the selective advantage and reversing the route of vancomycin resistance evolution, and to treat VREfm associated infections.

2022-05-20 | PXD030906 | Pride

Collateral Sensitivity Pseudomonas

Project description:Phenotypic convergence in response to drug exposure supports exploitation of collateral sensitivity to counter drug resistance

| PRJEB22929 | ENA

Evolutionary stability of collateral sensitivity to antibiotics in the model pathogen Pseudomonas aeruginosa.

Project description:Evolution is at the core of the impending antibiotic crisis. Sustainable therapy must thus account for the adaptive potential of pathogens. One option is to exploit evolutionary trade-offs, like collateral sensitivity, where evolved resistance to one antibiotic causes hypersensitivity to another one. To date, the evolutionary stability and thus clinical utility of this trade-off is unclear. We performed a critical experimental test on this key requirement, using evolution experiments with Pseudomonas aeruginosa, and identified three main outcomes: (i) bacteria commonly failed to counter hypersensitivity and went extinct; (ii) hypersensitivity sometimes converted into multidrug resistance; and (iii) resistance gains frequently caused re-sensitization to the previous drug, thereby maintaining the trade-off. Drug order affected the evolutionary outcome, most likely due to variation in the effect size of collateral sensitivity, epistasis among adaptive mutations, and fitness costs. Our finding of robust genetic trade-offs and drug-order effects can guide design of evolution-informed antibiotic therapy.

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