Reversal of microRNA-150 silencing disadvantages crizotinib-resistant NPM-ALK-positive cell growth.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Coralie Hoareau-Aveilla
PROVIDER: E-GEOD-69836 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:We used bisulfite conversion and Illumina sequencing to analyse miR-150 DNA methylation pattern lost in cells treated with decitabine, a demethylating agent, Crizotinib, an inhibitor of of ALK activity or siALK
2015-08-01 | GSE69836 | GEO
Project description:The non-small cell lung cancer (NSCLC) cell line HCC827 harbors an activating EGFR mutation (exon 19 deletion) that confers sensitivity to the FDA-approved EGFR inhibitor erlotinib. By applying the ClonTracer barcoding system, we were able to show the presence of pre-existing sub-populations in HCC827 that contribute to erlotinib resistance. Prior studies implicated that MET amplification confers resistance to erlotinib in this cell line. Therefore we examined the effects of the c-Met inhibitor crizotinib on the barcoded HCC827 population when treated either sequentially or simultaneously with both inhibitors. Despite the significant reduction in barcode complexity, the erlotinib/crizotinib combination treatment failed to eradicate all of the resistant clones implying the presence of an erlotinib/crizotinib dual resistant subpopulation. We performed transcriptome profiling (RNA-seq) to elucidate the potential resistance mechanisms of the dual resistant subpopulation in comparison to vehicle-treated or single agent erlotinib-resistant HCC827 cell populations as controls. mRNA profiling of the subpopulations of human NSCLC cell line HCC827 that contribute to EGFR inhibitor erlotinib and MET inhibitor crizotinib resistance
2014-10-07 | E-GEOD-62118 | biostudies-arrayexpress
Project description:Background: Tyrosine kinase inhibitors (TKIs) are widely used for treating solid and hematologic malignancies. However, their efficacy is frequently short lived, warranting the search for safe potentiation strategies. Short courses of fasting were shown to sensitize cancer cells to chemo- and radiotherapy while increasing the resistance of healthy tissues to the same agents. The purpose of this study was to assess the potential of fasting to increase the efficacy of TKIs. Methods: starvation-mimicking culture conditions were studied for their ability to potentiate the effects of Epidermal Growth Factor Receptor (EGFR), Human Epidermal Growth Factor Receptor 2 (HER2), Anaplastic Lymphoma Kinase (ALK) and multitarget TKIs in terms of cancer cell growth, signaling cascades inhibition, and changes in gene expression profile in TKI-sensitive cancer cells. In vivo, the activity of crizotinib or regorafenib, weekly cycles of fasting, or their combination was compared in tumor xenografts models. Results: In vitro, starvation-mimicking culture conditions increased the ability of TKIs to block cancer cell growth and to inhibit the mitogen-activated protein kinase (MAPK) signaling pathway. At the gene expression profile level, starvation and crizotinib led to similar changes, but their combination strengthened Rb-, MYC-, and E2F-dependent transcription inhibition. In vivo, both TKIs and cycles of fasting slowed tumor growth, but, when combined, they were significantly more effective than either type of treatment alone. Conclusions: Cycles of fasting or of specifically designed fasting-mimicking diets should be evaluated in clinical studies as a means to potentiate the activity of TKIs in clinical use. RNA was collected from H3122 cells in 4 different conditions: serum, starvation, treated with Crizotinib, starvation and treated with Crizotinib. Each condition was run in quadruplicate
2016-07-03 | E-GEOD-62663 | biostudies-arrayexpress
Project description:Abstract The infection of drug resistant bacteria seriously threats to public health, which makes it more urgent to find novel antibacterial compounds. Compared with traditional development approaches, drug repurposing provides a faster and more effective strategy to find new antimicrobial agents. Here, we screened an FDA-approved small-molecule library upon S. aureus, and identified crizotinib as an antimicrobial agent. We confirmed the antibacterial activities of crizotinib in vitro and in vivo by MIC, growth curve, SEM and mice experiment. At the same time, crizotinib also showed low tendency to develop resistance. Mechanistically, quantitative proteomics, bioinformatics analyses, qRT-PCR and flow cytometry biochemical validation experience confirmed that crizotinib exerted its antibacterial effects by interfering pyrimidine metabolism and disrupting DNA synthesis eventually. Furthermore, our data from drug affinity responsive target stability, bio-layer interferometry and a series of functional assays demonstrated that crizotinib could target PyrG directly in pyrimidine metabolism pathway. Taken together, our results indicated that crizotinib could be a potential antimicrobial agent to treat Gram-positive bacterial infections in the future.
2022-03-10 | PXD029546 | Pride
Project description:MET amplification is present in 20% of gastric cancers and has been confirmed as a therapeutic target in clinical trials. The molecular mechanisms of response and resistance to MET inhibitors are not well understood. We investigated the determinants of MET dependency in human gastric cancer. MET inhibition inhibited proliferation and induced cell death only in MET-amplified gastric cancer cell lines. The effects on growth arrest were stronger than the effects on cell death. To identify possible resistance mechanisms, we performed whole-genome mRNA expression profiling. Molecular changes related to autophagy were among the top alterations observed. Consistent with these findings, autophagy levels increased in a concentration-dependent manner when MET-amplified cells were exposed to crizotinib. Autophagy inhibition caused a dramatic decrease in apoptosis in one of the MET-amplified cell lines (MKN45) but not in the other (SNU-5). Because autophagy may provide energy in cells subjected to growth factor deprivation, we explored the effects of MET or autophagy inhibition on cellular ATP levels. This revealed that autophagy-dependent ATP production was selectively required for apoptosis in the MKN45 cells and that chemical ATP depletion mimicked the effects of autophagy inhibition to block cell death. Overall, the data reveal a novel relationship between ATP depletion and resistance to MET inhibitor-induced cell death. Our observations suggest that autophagy inhibitors could have unintended consequences when they are combined with growth factor receptor inhibitors in tumors that require autophagy-dependent ATP production for apoptosis. 12 samples triplicate samples of SNU-5 and MKN45 +/- criztonib for 24 hours
2016-05-13 | E-GEOD-77320 | biostudies-arrayexpress
Project description:Despite the initial benefit of the tyrosine kinase inhibitors targeting ALK gene fusions in non-small cell lung cancer, resistance to ALK inhibitors is almost inevitable. To determine the acquired resistance mechanism to ALK inhibition, we generated crizotinib-resistant ALK lines by chronically treating H3122 cells (driven by EML4-ALK) with an ALK inhibitor, crizotinib for approximately 3 months. RNA-seq and differential expression analyses were performed to determine the transcriptional changes of H3122-CR cells in comparison to parental H3122 cells. Because we demonstrated EGFR could mediate the early adaptive resistance to crizotinib, we further explored the mechanism that contributes to the resistance to the combination of crizotinib and afatinib. H3122-CAR (crizotinib and afatinib-resistant) cells were generated by treating them with a combination of crizotinib and afatinib for approximately 6 months and then profiled by RNA-seq to determine the associated transcriptional reprogramming.
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Project description:SW480 cells were treated with 2uM crizotinib for 72h (versus DMSO)
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Project description:TGFb and/or crizotinib were treated on A549 cell line to understand molecular mechanisms of action of crizotinib in TGF signaling pathway in lung cancer through gene expression profile data.
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Project description:In this study we have analysed the transcription profile of ALK rearranged cell lines (COST, DEL, JB6, KARPAS, SR786, SUPM2, TS). The analysis was done on untreated cell lines and on the te same cell lines surviving to progressive increasing addition of crizotinib to the culture medium. Crizotinib concentration was progressively increased to reach a final concentration of 1 μM. The resulting pool of resistant cells (designated crizotinib-resistant (CR)) were maintained in RPMI with 10% FBS containing 0.5-1 μM crizotinib.
2022-12-31 | GSE173306 | GEO
Project description:We used whole bodies of four different adult fire ant morphs (alate queens, workers, haploid males, and diploid males) from a single polygyne colony to generate single-base resolution DNA methylation maps. DNA was extracted from whole bodies of individual males, individual queens, and pooled workers. Bisulfite conversion and sequencing was performed by Beijing Genomics Institute (Shenzhen, China). Unmethylated enterobacteria phage lambda DNA (GenBank accession: J02459.1) was added to each genomic DNA sample as a control for bisulfite conversion efficiency.
2013-03-27 | E-GEOD-39959 | biostudies-arrayexpress