Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Gene expression profiles of an ALK-fusion driven cell line and its derivatives resistant to crizotinib alone or resistant to crizotinib plus afatinib

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE239666 | GEO | 2023/07/31

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Analysis of ALK TKI sensitive and ALK TKI resistant isogenic pairs of H3122 (EML4-ALK E13;A20) cells

Project description:Starting with H3122 cells, which harbor the EML4-ALK E13;A20 fusion and are known to be sensitive to ALK tyrosine kinase inhibitors, we generated isogenic pairs of ALK TKI sensitive and ALK TKI resistant cell lines using established methods (see Chmeliecki, J et al Science Trans Med 2011). We modeled resistance against the currently FDA approved ALK TKI, crizotinib (also called PF-1066). We also modeled resistance against a novel more potent ALK inhibitor, X-376 (ref: Lovly, CM et al Cancer Research 2011). We compared gene expression profiles between the 'parental' (ALK TKI sensitive) H3122 cells and the drug resistant cells (H3122 CR for Crizotinib resistant cells and H3122 XR for X-376 resistant cells).

2014-07-14 | GSE49508 | GEO

YAP activation mediates acquired resistance to ALK inhibitor in ALK rearranged non–small cell lung cancer

Project description:To investigate a possible candidate for overcoming the acquired resistance to ALK-TKI, we established an in vitro model of acquired resistance to crizotinib (H3122-CR) by exposing EML4-ALK–positive H3122 lung cancer cells to increasing doses of crizotinib.

2019-12-31 | GSE117181 | GEO

Fasting potentiates the anticancer activity of Crizotinib

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

Deacetylation of miRNA-34a and miRNA-449 induce epithelial-mesenchymal transition and acquired resistance to ALK inhibitors

Project description:Treatment with ALK tyrosine kinase inhibitors often elicits profound initial antitumor responses in ALK fusion-positive patients with lung adenocarcinoma. However, patients invariably develop acquired resistance to ALK inhibitors. In this study, we aimed to identify molecular events that limit the durable response to ALK inhibition using genetic and epigenetic approaches. To identify novel mechanisms of acquired resistance to ALK inhibitors, we established in vivo and in vitro models of acquired resistance to ceritinib and crizotinib using H3122 and H2228 cells. For in vivo model, mice with established H3122-derived tumors were treated with four doses of ceritinib (control, 75mg/kg, 87.5mg/kg, 100mg/kg) to derive ceritinib-resistant tumors.

2018-05-28 | GSE81261 | GEO

Deacetylation of miRNA-34a and miRNA-449 induces epithelial-mesenchymal transition and acquired resistance to ALK inhibitors

Project description:Treatment with ALK tyrosine kinase inhibitors often elicits profound initial antitumor responses in ALK fusion-positive patients with lung adenocarcinoma. However, patients invariably develop acquired resistance to ALK inhibitors. In this study, we aimed to identify molecular events that limit the durable response to ALK inhibition using genetic and epigenetic approaches. To identify novel mechanisms of acquired resistance to ALK inhibitors, we established in vivo and in vitro models of acquired resistance to ceritinib and crizotinib using H3122 and H2228 cells. For in vivo model, mice with established H3122-derived tumors were treated with four doses of ceritinib (50mg/kg, 75mg/kg, 87.5mg/kg, 100mg/kg) to derive ceritinib-resistant tumors.

2018-05-28 | GSE97646 | GEO

A genome-scale CRISPR-Cas9 loss-of-function screen in ALCL cells treated with crizotinib

Project description:We used a CRISPR-Cas9-based genome-wide guide RNA (sgRNA) library to identify genes responsible for driving drug resistance in ALK+ ALCL cells under crizotinib treatment.We screened 4 diffrerent ALK+ ALCL cell lines, TS, SU-DHL1, COST and KARPAS299. Every cell line was transduced with GeCKO A and GeCKO B sgRNA libraries separately. After puromycin selection, cells were splitted into 3 groups: Day 0 (baseline time point), crizotinib treated group (treated for 14 days) and DMSO treated group (treated for 14 days). TS and SU-DHL1 cells were treated with 40nM criztonib for 14 days and at the end of this period crizotinib concentration was increased to 80nM. COST cells received 50nM crizotinib for 14 days. KARPAS299 cells first received 50nM crizotinib for 14 days and at the end of this period crizotinib concentration was increased to 100nM. Crizotinib concentrations were determined based on their sensitivity for crizotinib for each cell line. The screening was repeated twice for TS and SU-DHL1 ALK+ ALCL cells. DNA isolotation was performed from all groups and each sgRNA sequence served as a barcode for Next Generation Illumina-based DNA sequencing. We compared enriched sgRNA sequences between Day 0 and DMSO conditions. We found that while PTPN2 was a top hit for all 4 ALK+ ALCL cells, PTPN1 was a top hit for TS and SU-DHL1 cells. We subsequently validated roles of PTPN1 and PTPN2 in crizotinib resistance separately. We demonstrated that both PTPN1 and PTPN2 can drive crizotinib resistance in ALK+ ALCL cells. In this study, we found two phosphatases, PTPN1 and PTPN2, involved in drug resitance in ALK+ ALCL using a CRSIPR Cas9-based screening approach. These two phosphatases regulate ALK phospharylation and therefore affect downstream signalling pathways involved in tumor growth and proliferation.

2023-03-15 | GSE152926 | GEO

A comprehensive analysis of metabolomics and transcriptomics reveals a novel crizotinib resistance mechanism in non-small cell lung cancer

Project description:Crizotinib is a first-line targeted therapy against EML4-ALK fusion in non-small cell lung cancer (NSCLC), but the increased resistance limits its clinical application. However, the mechanisms underlying such resistance are largely unexplored. The present study identified ALK protein overexpression in crizotinib-resistant H3122CR cells through immunoblotting. Then, liquid chromatography tandem mass spectrometry-based metabolomics was adopted to investigate metabolic responses. Crizotinib resistance was associated with the reduction of the total lipid content and the increase of organic acid, featuring the upregulation of lipid metabolism. Fatty acid β-oxidation pathway reprogrammed crizotinib-sensitive metabolome to crizotinib-resistant metabolome, resulting in crizotinib resistance. These findings reveal a previously unknown mechanism of crizotinib resistance and suggest promising applications of this approach in prognostic prediction and tailored therapeutics of NSCLC patients.

2021-10-31 | GSE186767 | GEO

Reversal of microRNA-150 silencing disadvantages crizotinib-resistant NPM-ALK-positive cell growth.

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

Reversal of microRNA-150 silencing disadvantages crizotinib-resistant NPM-ALK-positive cell growth.

2015-08-01 | E-GEOD-69836 | biostudies-arrayexpress

Gene expression profiles of an ALK-fusion driven cell line and its derivatives resistant to crizotinib alone or resistant to crizotinib plus afatinib

Project description:Gene expression profiles of an ALK-fusion driven cell line and its derivatives resistant to crizotinib alone or resistant to crizotinib plus afatinib

| PRJNA1000507 | ENA

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data