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Profiling non-small cell lung carcinoma cell line HCC827 treated with erlotinib

ABSTRACT: The non-small cell lung carcinoma (NSCLC) HCC827 cell line is an established preclinical model for tyrosine kinase inhibitors. To be able to better understand the differences in response between individual cells, we performed treatment of HCC827 cells grown in cell culture with erlotinib followed by Drop-seq. We were able to clearly distinguish cells that were treated with the drug from untreated cells, and we discovered different cell populations within the treated cells, likely reflecting heterogeneity of drug resistant cells. We were able to identify specific biomarkers, as preferentially expressed genes, for each cell population. The results of our study will address preexisting and acquired drug resistance that limits clinical usefulness of targeted strategies, particularly in NSCLC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE134837 | GEO | 2020/12/19

REPOSITORIES: GEO

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Charaterization of genetic alterations and gene expression signatures found in erlotinib-resistant and erlotinib/crizotinib dual-resistant HCC827 subpopulations

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

Charaterization of genetic alterations and gene expression signatures found in erlotinib-resistant and erlotinib/crizotinib dual-resistant HCC827 subpopulations

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Single cell RNA-seq profiling of erlotinib-resistant PC9 cells

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2020-12-19 | GSE149214 | GEO

Profiling non-small cell lung carcinoma cell line PC9 treated with erlotinib using 10x Genomics

Project description:The non-small cell lung carcinoma (NSCLC) PC9 cell line is an established preclinical model for tyrosine kinase inhibitors. To be able to better understand the differences in response between individual cells, we performed treatment of PC9 cells grown in cell culture with erlotinib followed by 10x Genomics. We were able to clearly distinguish cells that were treated with the drug from untreated cells, and we discovered different cell populations within the treated cells, likely reflecting heterogeneity of drug resistant cells. We were able to identify specific biomarkers, as preferentially expressed genes, for each cell population. The results of our study will address preexisting and acquired drug resistance that limits clinical usefulness of targeted strategies, particularly in NSCLC.

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Profiling non-small cell lung carcinoma cell line PC9 treated with erlotinib

Project description:The non-small cell lung carcinoma (NSCLC) PC9 cell line is an established preclinical model for tyrosine kinase inhibitors. To be able to better understand the differences in response between individual cells, we performed treatment of PC9 cells grown in cell culture with erlotinib followed by Drop-seq. We were able to clearly distinguish cells that were treated with the drug for five different time points from untreated cells, and we discovered different cell populations within the treated cells, likely reflecting heterogeneity of drug resistant cells. We were able to identify specific biomarkers, as preferentially expressed genes, for each cell population. The results of our study will address preexisting and acquired drug resistance that limits clinical usefulness of targeted strategies, particularly in NSCLC.

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Profiling non-small cell lung carcinoma cell line PC9 treated with etoposide, erlotinib and its combination with crizotinib

Project description:The non-small cell lung carcinoma (NSCLC) PC9 cell line is an established preclinical model for tyrosine kinase inhibitors. To be able to better understand the differences in response between individual cells, we performed treatment of PC9 cells grown in cell culture with etoposide, erlotinib and its combination with crizotinib, followed by Drop-seq. The addition of crizotinib was guided by our previous data that an erlotinib-resistant drug population may be sensitive to crizotinib. To better understand the common events in drug resistance, we compared the resistant cell populations arising from the treatment with etoposide and from the treatment with erlotinib. The results of our study will address emerging drug resistance that limits clinical usefulness of conventional and targeted strategies, particularly in NSCLC.

2020-12-19 | GSE149215 | GEO

Genome-wide map of H3K4me3 in erlotinib-resistant PC9 cells.

Project description:The non-small cell lung carcinoma (NSCLC) PC9 cell line is an established preclinical model for tyrosine kinase inhibitors. Recent evidence suggests that the H3K4 demethylase KDM5A protein is required for emerging drug-resistant cell populations. To better understand the dependence of cell survival on H3K4me3 level, we treated the EGFR-mutant PC9 cells with erlotinib and performed ChIP-seq analysis using H3K4me3 antibodies. We were able to identify genomic regions that exhibit decreased H3K4me3 in drug-treated cells. The results of this study will help to address clinical usefulness of KDM5A-targeted strategies in overcoming drug resistance, particularly in NSCLC.

2020-12-19 | GSE148461 | GEO

The HDAC inhibitor panobinostat acts as a sensitizer for erlotinib activity in EGFR mutated and wildtype NSCLC cells

Project description:The receptor tyrosine kinase (RTK) EGFR is overexpressed and mutated in NSCLC. These mutations can be targeted by RTK inhibitors (TKIs), such as erlotinib. Chromatin-modifying agents offer a novel therapy approach by sensitizing tumor cells to TKIs. The NSCLC cell lines HCC827 (EGFR mutant, adenocarcinoma), A549 (EGFR wt, adenocarcinoma) and NCI-H460 (EGFR wt, large cell carcinoma) were analyzed by SNP6.0 array. Changes in proliferation were quantified by WST-1 assay, apoptosis by Annexin V/7-AAD flow cytometry and histone marks (acH3, H3K4me1,-2,-3) by immunoblotting. Expectedly, the EGFR wt cell lines A549 and NCI-H460 were insensitive to the growth-inhibiting effect of single-agent erlotinib (IC50 70-100µM), compared to HCC827 (IC50 <0.02μM). Treatment with panobinostat diminished growth to <50% in both EGFR wt and <30% in HCC827 cells. The combination of both drugs significantly reduced proliferation by ≥70% in A549, >95% in HCC827, but not further in NCI-H460. Panobinostat alone induced differentiation and expression of p21WAF1/CIP1 and p53 in all three cell lines, with almost no further increase when combined with erlotinib. In contrast, combination treatment additively decreased pERK, pAKT and pEGFR in A549, and synergistically induced acH3 in both adenocarcinoma lines. Surprisingly, we also saw an induction of H3K4 methylation marks in all three cell lines. In conclusion, panobinostat synergistically sensitized lung adenocarcinoma cells to the antiproliferative effects of erlotinib. Since single-agent erlotinib has only modest clinical effects in adenocarcinoma EGFR wt patients, combination therapy with an HDACi might offer a promising therapy approach to extend this activity. Copy-number analysis of three NSCLC cell lines HCC827, A549 and NCI-H460 (in unicates) was performed according to protocol by Affymetrix Genome-Wide Human SNP-Array 6.0.

2014-12-03 | E-GEOD-63784 | biostudies-arrayexpress

Gene expression profiling of generated Erlotinib-resistant (ER) cell lines

Project description:Targeted therapies have provided advantages to cancer patients, but these therapies are limited by differential responses and developed resistance. To discover mechanisms of resistance, we developed drug-resistant cell lines and have their gene expressions profiled and compared. HCC827 cells, which were initially sensitive to Erlotinib treatment, are subjected to Erlotinib treatment. Two clonal populations that resistant to Erlotinib resulted.

2012-06-15 | E-GEOD-38121 | biostudies-arrayexpress

The HDAC inhibitor panobinostat acts as a sensitizer for erlotinib activity in EGFR mutated and wildtype NSCLC cells

Project description:Background: The receptor tyrosine kinase (RTK) EGFR is overexpressed and mutated in NSCLC. These mutations can be targeted by RTK inhibitors (TKIs) such as erlotinib. Chromatin-modifying agents may offer a novel therapeutic approach by sensitizing tumor cells to TKIs. Methods: The NSCLC cell lines HCC827 (EGFR mutant, adenocarcinoma), A549 (EGFR wt, adenocarcinoma) andNCI-H460 (EGFR wt, large cell carcinoma) were analyzed by SNP6.0 array. Changes in proliferation after panobinostat (LBH-589, PS) and erlotinib treatment were quantified by WST-1 assay and apoptosis by Annexin V/7-AAD flow cytometry. Abundance of target proteins and histone marks (acH3, H3K4me1/2/3) was determined by immunoblotting. Results: As expected, the EGFR wt cell lines A549 and NCI-H460 were quite insensitive to the growth-inhibitory effect of single-agent erlotinib (IC50 70-100 μM), compared to HCC827 (IC50 < 0.02 μM). PS treatment diminished growth to <50 % in both EGFR wt cells, and <30 % in HCC827. The combination of both drugs reduced proliferation by >95 % in HCC827, ≥70 % in A549, but not further in NCI-H460. PS alone induced differentiation and expression of p21WAF1/CIP1 and p53 and decreased CHK1 in all three cell lines, with almost no further effect when combined with erlotinib. In contrast, combination treatment additively decreased pEGFR, pERK, pAKT in A549, and synergistically induced acH3 in both adenocarcinoma lines. Surprisingly, we saw an induction of H3K4 methylation marks after erlotinib treatment in HCC827 (and to a lesser extent in A549) that was even further enhanced by combination with PS. Conclusion: We were able to show that PS synergistically sensitized lung adenocarcinoma cells to the antiproliferative effects of erlotinib. Since single-agent erlotinib has only modest clinical effects in lung adenocarcinoma EGFR wt patients, its combination with an HDACi might offer a promising therapy approach.

2014-12-03 | GSE63784 | GEO

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