Acquired Extensive Drug Resistance in Tuberculosis
Ontology highlight
ABSTRACT:
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR789234_1.fastq.gz | Fastqsanger.gz | |||
| ERR789234_2.fastq.gz | Fastqsanger.gz | |||
| ERR789235_1.fastq.gz | Fastqsanger.gz | |||
| ERR789235_2.fastq.gz | Fastqsanger.gz | |||
| ERR789236_1.fastq.gz | Fastqsanger.gz |
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Project description:Acquired drug resistance and tumour relapse impacts the majority of patients being treated with tyrosine kinase inhibitors (TKIs) and remains a key challenge in modern anti-cancer therapy. The lack of clinically effective therapeutic strategies to overcome drug resistance represents a significant unmet need. Understanding the signalling pathways that drive drug resistance will facilitate the development of new salvage therapies to effectively treat patients with secondary TKI resistance. In this study, we utilise quantitative mass spectrometry to characterise the global phosphoproteomic alterations that accompany the acquisition of resistance to two FDA-approved multi-target TKIs, pazopanib and dasatinib, in the A204 rhabdoid tumour cell line. Our analysis finds that only a limited fraction of the quantified phosphoproteome (<10%) is altered upon the acquisition of drug resistance with pazopanib resistant cells displaying elevated phosphorylation levels in cytoskeletal regulatory pathways and dasatinib resistant cells showing an upregulation of components of the insulin receptor/IGF1-R signalling pathway. Drug response profiling with a targeted panel of small molecule inhibitors rediscovers several previously reported vulnerabilities associated with pazopanib and dasatinib resistance and identifies a new dependency to the second generation HSP90 inhibitor NVP-AUY-922. This study provides a useful resource detailing the candidate signalling determinants of acquired TKI resistance; and reveals a therapeutic approach of inhibiting HSP90 function as a means of salvage therapy to overcome pazopanib and dasatinib resistance.
2017-08-30 | PXD005536 | Pride
Project description:Anaplastic lymphoma kinase (ALK) inhibitors (ALKi) are effective in treating lung cancer patients with chromosomal rearrangement of ALK. However, continuous treatment with ALKi invariably leads to acquired resistance in cancer cells. In this study, we propose an efficient strategy to suppress ALKi resistance through a meta-analysis of transcriptome data from various cell models of acquired resistance to ALKi. We systematically identified gene signatures that consistently showed altered expression during the development of resistance and conducted computational drug screening using these signatures. We identified emetine as a promising candidate compound to inhibit the growth of ALKi-resistant cells. We demonstrated that this drug exhibited effectiveness in inhibiting the growth of ALKi-resistant cells, and further elucidated its mode of action through drug-induced RNA-seq data. Our transcriptome-guided systematic approach paves the way for efficient drug discovery to overcome acquired resistance to cancer therapy.
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Project description:An acquired vulnerability of drug resistant melanoma with therapeutic potential
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Project description:Although in vitro models have been a cornerstone of anti-cancer drug development, their direct applicability to clinical cancer research has actually been uncertain. Using a state-of-the-art Taqman-based qRT-PCR assay, we investigated the multidrug resistance (MDR) transcriptome of six cancer types, in both in vitro and in vivo samples. We studied 380 MDR genes, selected a priori based on an extensive curation of the literature published during the last three decades, in established cancer cell lines and clinical samples, either containing greater than 75% tumor cells or microdissected.
2011-11-16 | E-GEOD-30034 | biostudies-arrayexpress
Project description:This study was conducted to identify dysregulated genes associated with acquired resistance to chemotherapy. Endoscopic biopsy samples were collected from CF-treated metastatic gastric cancer patients prior to therapy and following the development of resistance to therapy.
2011-06-01 | E-GEOD-14209 | biostudies-arrayexpress
Project description:BackgroundIncreasing access to drugs for the treatment of multidrug-resistant (MDR) tuberculosis is crucial but could lead to increasing resistance to these same drugs. In 2000, the international Green Light Committee (GLC) initiative began to increase access while attempting to prevent acquired resistance.MethodsTo assess the GLC's impact, we followed adults with pulmonary MDR tuberculosis from the start to the end of treatment with monthly sputum cultures, drug susceptibility testing, and genotyping. We compared the frequency and predictors of acquired resistance to second-line drugs (SLDs) in 9 countries that volunteered to participate, 5 countries that met GLC criteria, and 4 countries that did not apply to the GLC.ResultsIn total, 832 subjects were enrolled. Of those without baseline resistance to specific SLDs, 68 (8.9%) acquired extensively drug-resistant (XDR) tuberculosis, 79 (11.2%) acquired fluoroquinolone (FQ) resistance, and 56 (7.8%) acquired resistance to second-line injectable drugs (SLIs). The relative risk (95% confidence interval [CI]) of acquired resistance was lower at GLC-approved sites: 0.27 (.16-.47) for XDR tuberculosis, 0.28 (.17-.45) for FQ, and 0.15 (.06-.39) to 0.60 (.34-1.05) for 3 different SLIs. The risk increased as the number of potentially effective drugs decreased. Controlling for baseline drug resistance and differences between sites, the odds ratios (95% CIs) were 0.21 (.07-.62) for acquired XDR tuberculosis and 0.23 (.09-.59) for acquired FQ resistance.ConclusionsTreatment of MDR tuberculosis involves substantial risk of acquired resistance to SLDs, increasing as baseline drug resistance increases. The risk was significantly lower in programs documented by the GLC to meet specific standards.
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Project description:While effective therapy is available for melanoma patients harbouring BRAF mutations, to date, the efficient therapeutic approaches for NRAS-mutant melanoma patients are limited. Therapeutic regimen involving combinatorial inhibition of MEK1/2 and CDK4/6 prove to be beneficial as targeted therapy for NRAS-mutant melanoma. Yet, only a subset of melanoma patients responded to this treatment, whereas acquired resistance eventually emerge in responders. Upon prolonged therapy with MEK1/2 and CDK4/6 inhibitors cells switch to fully drug-resistant or senescent phenotype in vitro. Consequently, there is a necessity to portray cell populations sensitive to targeted therapy, but also cell transitions associated with NRAS-mutant melanoma resistance. To define transcriptional states arising under indicated therapy and cell fate decisions governing resistance, we performed single-cell RNA sequencing at four distinguished time points during treatment. In this study, we identified a cell population highly enriched in calcium signalling, among others, associated with positive drug response. In particular, prolonged expression of ATP-gated ion channel P2RX7 was related to a senescent-like phenotype. Next, we described an immune-like melanoma state that acquired drug resistance and re-enter the cell cycle under treatment, as well as cell populations with intrinsic potential to evade drug pressure.
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Project description:Accumulating evidence indicates adaptive cellular reprogramming is a major contributor to disease recurrence and acquired drug resistance in cancer. Here we show that chronic drug exposure results in a multi-state metabolic and epigenetic adaption that allows cancer cells to regain proliferative capacity and eventually develop permanent drug resistance. Specifically, the escape from the previously described slow cycling induced drug tolerant cell state is driven by transiently increased expression of O-GlcNAc transferase (OGT) linking metabolic to epigenetic changes by facilitating global H3K4me3 remodeling. This adaptive process can be blocked by genetic or pharmacological inhibition of OGT or concurrent activation of AMPK to prevent metabolic adaption, subsequent epigenetic remodeling and permanent acquired drug resistance. This novel metabolic and epigenetic remodeling process is also observed following oncogene induced stress and the OGT dependence of this adaptive process uncovered promising targets for combination therapy with current standard of care drugs that could significantly increase response duration and patient outcomes.
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Project description:PROTACs (Proteolysis-Targeting Chimeras) represent a revolutionary new class of drugs that selectively degrade proteins of interest from cells. PROTACs targeting oncogenes are avidly being explored for cancer therapies, with several currently in clinical trials. Drug resistance represents a significant challenge in cancer therapies, and the mechanism by which cancer cells acquire resistance to protein degraders remains poorly understood. Here, we applied proteomics approaches to elucidate resistance mechanisms to protein degrader therapies in cancer cells. Our studies revealed acquired resistance to degrader therapies in cancer cells can be mediated by upregulation of the ATP-dependent drug efflux pump MDR1. Degrader-resistant cells could be re-sensitized to PROTACs through co-administering MDR1 inhibitors. Notably, MDR1 is frequently overexpressed in cancer, and cancer cell lines overexpressing MDR1 exhibited intrinsic resistance to protein degraders, requiring co-treatment with MDR1 inhibitors to achieve protein degradation and therapeutic response. Notably, co-treatment of MDR1-overexpressing K-ras mutant colorectal cancer cells with MEK1/2 or K-ras degraders and the dual ErbB receptor/MDR1 inhibitor lapatinib exhibited potent drug synergy due to simultaneous blockade of MDR1 activity and ErbB receptor-driven resistance. Together, our findings showed overexpression of MDR1 can promote both intrinsic and acquired resistance to protein degraders in cancer cells and that concurrent blockade of MDR1 will likely be required to achieve durable protein degradation and therapeutic response.
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Project description:Here we investigated whether a combination of cell-free infection and cell-to-cell spread confers a selective advantage in the evolution of resistance to an inhibitor relative to cell-to-cell spread alone due to the stronger selection pressure against drug sensitive virus. We propagated HIV infection using coculture of infected with uninfected cells in the face of the reverse transcriptase inhibitor efavirenz (EFV), and compared the effect on drug resistance evolution of including one cycle of cell-free infection. In the presence of a single cell-free infection step, we obtained earlier evolution of resistance to EFV. When we increased selective pressure by adding emtricitabine (FTC as a second drug, infection with the cell-free step evolved multidrug resistance and was able to replicate, while infection without a cell-free step failed to evolve multidrug resistance. In conclusion, our results suggest that, HIV cell-to-cell spread has a decreased capacity to rapidly evolve resistance to inhibitors, which is conferred by cell-free infection.
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