Gene expression profiling of generated Erlotinib-resistant (ER) cell lines
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Elton Chan
PROVIDER: E-GEOD-38121 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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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:We were interested in characterizing the transcriptional changes that occur on a genome-wide scale following treatment of EGFR-mutant lung cancer cells with targeted therapies. HCC827 human lung cancer cells harboring an amplified EGFR allele with an activating in frame deletion of 15 nucleotides in exon 19 were treated in triplicate with 1uM erlotinib (EGFR inhibitor), AZD-6244 (MEK inhibitor) or BEZ-235 (PI3-Kinase/mTOR inhibitor) for 6 hours, followed by total mRNA isolation and whole transcriptome analysis using Affymetrix U133 Plus 2.0 expression arrays.
2015-02-25 | E-GEOD-51212 | biostudies-arrayexpress
Project description:Microarray expression analysis to identify global changes in transcription in response to RAF inhibition. Genes under RAF control were identified in a panel of BRAFV600E tumor cells, following the short-term inhibition of RAF using a pan-RAF kinase inhibitor, PLX4032 (Plexxikon). For comparison with changes in gene expression in response to MEK inhibition using PD0325901 (Pfizer), the following array data was referenced: (http://www.ncbi.nlm.nih.gov/geo/ (accession no. GSE10086)). Cell lines growing in culture (n=5) were treated with the RAF inhibitor PLX4032 (250nM or 1000nM) or vehicle alone (0.1% DMSO) as control, for eight hours.
2010-07-18 | E-GEOD-20051 | biostudies-arrayexpress
Project description:In comparing gene expression of normal and CML CD34+ quiescent (G0) and proliferating (G1/S/G2/M) cells, 292 genes were down-regulated and 192 genes were up-regulated in the CML G0 cells. The differentially expressed genes were grouped according to their reported functions and correlations were sought with biological differences previously observed between the same groups. The most apparent correlations include: i) Normal and CML G0 cells are more primitive than G1/S/G2/M cells; ii) CML G0 cells are in a more advanced stage of development and more poised to begin proliferating than normal G0 cells; iii) When CML G0 cells are stimulated to proliferate, they undergo further differentiation and maturation more rapidly than normal G0 cells, but both granulopoiesis and erythropoiesis are less efficient than normal; iv) Whereas normal G0 cells form only granulocyte/monocyte (GM) colonies when stimulated by cytokines, CML G0 cells consistently form a combination of GM and erythroid clusters and colonies; and v) Prominin-1 (CD133) is the gene most down-regulated in CML G0 cells and its down-regulation appears to be associated with the spontaneous formation of erythroid colonies by CML progenitors without EPO. The gene most over-expressed in CML G0 cells is LepR, but its role in contributing to the myeloid expansion and other abnormalities is unknown. It was hoped that LepR might serve as a therapeutic target, but leptin had no stimulatory or inhibitory effect on either normal or CML G0 cells, our attempts to make a specific LepR antibody were unsuccessful, and no other potentially targetable over-expressed surface antigens were identified. A total of eight patients diagnosed with Ph+ CML (three in accelerated phase and five in chronic phase) were used in this study. The CML samples were all obtained from patients hospitalized at the Memorial Sloan Kettering during the period 1990-2006. The four normal bone marrow samples were purchased from Cambrex (Cambrex Bio Science Rockland,Inc., Rockland, Maine 04841, USA).
2010-10-16 | E-GEOD-24739 | biostudies-arrayexpress
Project description:In this study, we explored the mechanisms of hypoxia-induced EGFR TKI resistance in non-small cell lung cancer (NSCLC) harbored activating EGFR mutation. The NSCLC cell lines were exposed to normorxia or 1% oxygen for 4 weeks, and then we tested EGFR TKI sensitivity in normoxic and hypoxic NSCLC cell lines. In this microarray experiment, we used normoxic HCC827 and hypoxia-induced gefitinib resistant clones, C2-3 and C2-10. Those clones were selected with gefitinib treatment after the HCC827 were exposed to 1% oxygen for 4 weeks, and the HCC827 C2-3 and C2-10 clones were selected at random for this study.
2020-12-19 | E-MTAB-9452 | biostudies-arrayexpress
Project description:Aim: The goals of this study were to identify transcriptomic changes that arise in basal-like breast cancer cells during the development of resistance to epidermal growth factor receptor inhibitors (EGFRi) and to identify drugs that are cytotoxic once EGFRi resistance occurs. Methods: Human patient-derived xenografts (PDXs) were grown in immunodeficient mice and were treated with a set of EGFRi; the EGFRi erlotinib was selected for more expansive in vivo studies. Single-cell RNA sequencing was performed on mammary tumors from the basal-like PDX WHIM2 that was treated with vehicle or erlotinib for nine weeks. The PDX was then subjected to long-term erlotinib treatment in vivo and through serialserially passaging, an erlotinib-resistant subline of WHIM2 was generated. Bulk RNA-sequencing was performed on parental and erlotinib-resistant tumors. In vitro high-throughput drug screening with >500 clinically used compounds was performed on parental and erlotinib-resistant cells. Previously published bulk gene expression microarray data from MMTV-Wnt1 tumors were contrasted with the WHIM2 PDX data. Results: Erlotinib effectively inhibited WHIM2 tumor growth for ~four weeks. Compared to untreated cells, single-cell RNA sequencing revealed that a greater proportion of erlotinib-treated cells were in the G1 phase of the cell cycle. Comparison of WHIM2 and MMTV-Wnt1 RNA level data revealed a set of 37 overlapping genes that were differentially expressed in the erlotinib-resistant subsets of WHIM2 and MMTV-Wnt1 tumors. Comparison of all three data types revealed five genes that were upregulated across all erlotinib-resistant samples: IL19, KLK7, LCN2, SAA1, and SAA2. Despite transcriptomic differences, parental and erlotinib-resistant WHIM2 displayed similar responses to the majority of drugs assessed for cytotoxicity in vitro. Conclusion: This study identified transcriptomic changes arising in erlotinib-resistant basal-like breast cancer. Interestingly, four of the five genes that were found to be upregulated in the basal-like erlotinib-resistant samples were also upregulated in erlotinib-resistant non-small cell lung cancer samples. These gene signatures could be used to identify basal-like breast cancer patients that would best respond to EGFRi. Future studies should explore the predictive capacity of these gene signatures as well as how these differentially expressed genes contribute to the development of EGFRi resistance.
2022-12-07 | GSE189324 | GEO
Project description:Aim: The goals of this study were to identify transcriptomic changes that arise in basal-like breast cancer cells during the development of resistance to epidermal growth factor receptor inhibitors (EGFRi) and to identify drugs that are cytotoxic once EGFRi resistance occurs. Methods: Human patient-derived xenografts (PDXs) were grown in immunodeficient mice and were treated with a set of EGFRi; the EGFRi erlotinib was selected for more expansive in vivo studies. Single-cell RNA sequencing was performed on mammary tumors from the basal-like PDX WHIM2 that was treated with vehicle or erlotinib for nine weeks. The PDX was then subjected to long-term erlotinib treatment in vivo and through serialserially passaging, an erlotinib-resistant subline of WHIM2 was generated. Bulk RNA-sequencing was performed on parental and erlotinib-resistant tumors. In vitro high-throughput drug screening with >500 clinically used compounds was performed on parental and erlotinib-resistant cells. Previously published bulk gene expression microarray data from MMTV-Wnt1 tumors were contrasted with the WHIM2 PDX data. Results: Erlotinib effectively inhibited WHIM2 tumor growth for ~four weeks. Compared to untreated cells, single-cell RNA sequencing revealed that a greater proportion of erlotinib-treated cells were in the G1 phase of the cell cycle. Comparison of WHIM2 and MMTV-Wnt1 RNA level data revealed a set of 37 overlapping genes that were differentially expressed in the erlotinib-resistant subsets of WHIM2 and MMTV-Wnt1 tumors. Comparison of all three data types revealed five genes that were upregulated across all erlotinib-resistant samples: IL19, KLK7, LCN2, SAA1, and SAA2. Despite transcriptomic differences, parental and erlotinib-resistant WHIM2 displayed similar responses to the majority of drugs assessed for cytotoxicity in vitro. Conclusion: This study identified transcriptomic changes arising in erlotinib-resistant basal-like breast cancer. Interestingly, four of the five genes that were found to be upregulated in the basal-like erlotinib-resistant samples were also upregulated in erlotinib-resistant non-small cell lung cancer samples. These gene signatures could be used to identify basal-like breast cancer patients that would best respond to EGFRi. Future studies should explore the predictive capacity of these gene signatures as well as how these differentially expressed genes contribute to the development of EGFRi resistance.
2022-12-07 | GSE189257 | 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.
2014-10-07 | GSE62118 | GEO
Project description:Given the recent reports on the role of AXL in mediating resistance to EGFR-targeted therapy, we generated cell line models of Erlotinib-resistance to investigate the effect of AXL inhibitors on EGFR TKI resistance. For this, EGFR-mutant PC9 cells were passed through a persister bottleneck by applying strong drug selection pressure to generate drug-tolerant erlotinib persister cells. We created four Erlotinib-resistant clones from one parental population; S1-34, S2-10, S2-17 and S2-30. Whole exome and RNA sequencing analyses were performed to probe the differences in Erlotinib-resistance mechanisms present in these persister-derived Erlotinib-resistant cells.
2022-04-13 | GSE191185 | GEO
Project description:Resistance to tyrosine kinase inhibitors (TKIs) presents a growing challenge in the development of therapeutic targets for cancers such as triple negative breast cancer (TNBC), where conventional therapies are ineffective for combatting systemic disease. Due to increased expression, the receptor tyrosine kinases EGFR (epidermal growth factor receptor) and c-Met are potential targets for treatment. However, targeted anti-EGFR and anti-c-Met therapies have faced mixed results in clinical trials due to acquired resistance. We hypothesize that the upregulation of kinases within the EGFR and c-Met signaling axes contribute to the development of acquired erlotinib and cabozantinib resistance. To test this, we developed two separate models for cabozantinib and erlotinib resistance using the MDA-MB-231 and MDA-MB-468 cell lines, respectively. With a SILAC (Stable Isotope Labeling of Amino acids in Cell Cul-ture)-labeled quantitative mass spectrometry proteomics approach, we assessed the effects of erlotinib- or cabozantinib resistance on the phosphoproteome, proteome and kinome. Using this integrated proteomics approach, we identified several potential kinase mediators of cabozan-tinib-resistance and confirmed the contribution of AKT1 to erlotinib-resistance in TNBC resistant cell lines.
2024-06-28 | PXD043368 | JPOST Repository