Gene expression profiling after cetuximab treatment of HNSCC tumors
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE109756 | GEO | 2020/01/17
REPOSITORIES: GEO
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Project description:To filter the up-regulated gene induced by miR-451a overexpression and in cetuximab resistant HNSCC cell. We employed whole genome microarray. The HNSCC cell CAL27 was used as a control sample. CAL27_CTX, the cetuximab resistant CAL27 was compared with CAL27. The miR-451a overexpressed CAL27_451a sample was compared with the CAL27_NC sample. CAL27_CTX and CAL27_451A samples were collected after 48h of cetuximab treatment. The microarray results were taken together with ChIRP-seq analysis and bioinformatics analysis for miR-451a binding and enhancer analysis to eventually find the nuclear acticating target of miR-451a
2024-01-01 | GSE245159 | GEO
Project description:Unraveling the underlying mechanisms of cetuximab resistance in head and neck squamous cell carcinoma (HNSCC) is of major importance as many tumors remain non-responsive or become resistant. Out microarray results suggest that resistant cells still exhibit RAS-MAPK pathway signaling contributing to drug resistance, as witnessed by low expression of DUSP 5 and DUSP6, negative regulators of ERK1/2, and increased expression of AURKB, a key regulator of mitosis. Therefore, interrupting the RAS-MAPK pathway by an ERK1/2 inhibitor (apigenin) or an AURKB inhibitor (barasertib) might be a new strategy for overcoming cetuximab resistance in HNSCC 4 head and neck squamous cell carcinoma (HNSCC) cell lines were treated with either 15 nM cetuximab or PBS during 13 hours. For each cell line, differential gene expression was assessed between cetuximab and PBS treatments.
2014-09-18 | E-GEOD-61495 | biostudies-arrayexpress
Project description:Background: Identifying potential resistance mechanisms while tumour cells still respond to therapy is critical to delay acquired resistance. Methods: We generated the first comprehensive multi-omics, bulk and single-cell data in sensitive head and neck squamous cell carcinoma (HNSCC) cells to identify immediate responses to cetuximab. Two pathways potentially associated with resistance were focus of the study: regulation of receptor tyrosine kinases by TFAP2A transcription factor, and epithelial-to-mesenchymal transition (EMT). Results: Single-cell RNA-seq demonstrates heterogeneity, with cell-specific TFAP2A and VIM expression profiles in response to treatment and also with global changes to various signalling pathways. RNA-seq and ATAC-seq reveal global changes within 5 days of therapy, suggesting early onset of mechanisms of resistance; and corroborates cell line heterogeneity, with different TFAP2A targets or EMT markers affected by therapy. Lack of TFAP2A expression is associated with HNSCC decreased growth, with cetuximab and JQ1 increasing the inhibitory effect. Regarding the EMT process, short-term cetuximab therapy has the strongest effect on inhibiting migration. TFAP2A silencing does not affect cell migration, supporting an independent role for both mechanisms in resistance. Conclusion: Overall, we show that immediate adaptive transcriptional and epigenetic changes induced by cetuximab are heterogeneous and cell type dependent; and independent mechanisms of resistance arise while tumour cells are still sensitive to therapy.
2020-05-04 | GSE114446 | GEO
Project description:Patients with metastatic colorectal cancer were enrolled for treatment with cetuximab monotherapy. Transcriptional profiling was conducted on RNA from pre-treatment metastatic site biopsies to identify genes whose expression correlates with best clinical responses. Keywords: comparison of disease control group versus non-responder group of patients
2008-01-31 | GSE5851 | GEO
Project description:The identification of the potential mechanisms of resistance while tumor cells still respond to therapy is critical to develop combination therapies to delay acquired resistance. Cetuximab, an anti-EGFR therapy, is the only targeted therapy available for head and neck squamous cell carcinoma (HNSCC). We generated the first comprehensive multi-omics, bulk and single cell data in sensitive HNSCC cells to identify relevant transcriptional and epigenetic changes that are an immediate response to cetuximab in sensitive cells. These changes include genes from two pathways potentially associated with resistance: regulation of growth factor receptors through the transcription factor TFAP2A, and epithelial-to-mesenchymal transition (EMT) process. Single cell RNA-sequencing demonstrates inter-cell lines heterogeneity, with cell specific expression profiles of TFAP2A and VIM gene expression in cetuximab treated and untreated clones, and an independent role of each pathway. RNA-seq and ATAC-seq demonstrate that there are global transcriptional and epigenetic changes within the first five days of anti-EGFR therapy. We also experimentally verified that lack of TFAP2A reduces HNSCC growth in vitro and that this effect is enhanced with cetuximab and a stronger effect is observed with JQ1, an inhibitor of alternative receptor tyrosine kinases. Corroborating our scRNA-seq observation, TFAP2A silencing does not affect cell migration, supporting the lack of interplay with the EMT pathway. Overall, our study shows that the immediate adaptive transcriptional and epigenetic changes induced by cetuximab include relevant pathways associated with acquired resistance. Although heterogeneous, these changes can be targeted by a multiple-target drug as JQ1 that in combination with cetuximab in the early stage of treatment present better efficacy in controlling tumor growth.
2020-05-04 | GSE135604 | GEO
Project description:Abstract Background. Epidermal growth factor receptor (EGFR) is a targetable molecule in basal-like breast cancer, which comprises most “triple negative” breast cancer (TNBC), the only breast cancer subtype without established targeted therapy. Methods. In this randomized phase II trial, metastatic TNBC patients received the anti-EGFR antibody cetuximab (250mg/kg/week iv) with carboplatin (AUC2/wk iv) added on progression, or concomitant cetuximab + carboplatin. Molecular subtyping was done on archival specimens and those with accessible tumors provided fresh tissue, before and after 7-14 days of therapy, for microarray analyses to explore EGFR pathway inhibition. Results. Of 102 TNBC patients 74% were of the basal-like molecular subtype. Response rate to cetuximab was 6% (2/31), and was 16% (4/25) to cetuximab + carboplatin after progression. Upfront cetuximab + carboplatin produced responses in 17% (12/71); 31% responded or had prolonged disease stabilization. Time to progression was 2.1 months (95% CI 1.8-5.5) and overall survival 10.4 months (95% CI 7.7-13.1) for those treated with the combination regimen. Among 16 patients with evaluable serial biopsies, genomic patterns of the EGFR pathway showed activated status in 13 and inhibition by therapy in 5. Conclusions. While most TNBC were basal-like, a significant proportion were different subtypes. The aggressive nature of metastatic TNBC leads to limited survival. Despite a promising preclinical rationale and evidence of EGFR pathway activation in most, targeted treatment with cetuximab as a single agent had marginal activity and cetuximab added to carboplatin demonstrated modest activity. Serial biopsies as part of metastatic breast cancer studies are feasible, and this study confirmed that the EGFR pathway was inhibited by therapy in only a minority suggesting ligand-independent activation in most tumors. Tissue acquisition and drug selection based upon individualized pathway activation status should be an important part of future studies of TNBC. This series contains 36 microarrays that are from 18 patients with fresh frozen tissue available from the metastatic site. Pretreatment samples (Bx0) are available for two patients. Pretreatment and post single agent treatment (7-14 days after start of treatment with cetuximab; BxSingle) are available for three patients. Pretreatment and post combination treatment (7-14 days after start of treatment with cetuximab plus carboplatin; BxCombo) are available for eight patients. Two patients have a pretreatment sample, a sample after 7-14 days of treatment with single agent cetuximab, and a third sample 7-14 days on cetuximab plus carboplatin after switching to the combination arm upon progression on the single agent arm. Samples were hybridized with Stratagene common reference spiked with RNA from two breast cancer cell lines (ME16C and MCF-7) on Custom 1x44K Agilent microarrays. Arrays were scanned on an Axon 4000B scanner and analyzed with GenePix Pro software.
2012-07-13 | E-GEOD-23428 | biostudies-arrayexpress
Project description:The identification of the potential mechanisms of resistance while tumor cells still respond to therapy is critical to develop combination therapies to delay acquired resistance. Cetuximab, an anti-EGFR therapy, is the only targeted therapy available for head and neck squamous cell carcinoma (HNSCC). We generated the first comprehensive multi-omics, bulk and single cell data in sensitive HNSCC cells to identify relevant transcriptional and epigenetic changes that are an immediate response to cetuximab in sensitive cells. These changes include genes from two pathways potentially associated with resistance: regulation of growth factor receptors through the transcription factor TFAP2A, and epithelial-to-mesenchymal transition (EMT) process. Single cell RNA-sequencing demonstrates inter-cell lines heterogeneity, with cell specific expression profiles of TFAP2A and VIM gene expression in cetuximab treated and untreated clones, and an independent role of each pathway. RNA-seq and ATAC-seq demonstrate that there are global transcriptional and epigenetic changes within the first five days of anti-EGFR therapy. We also experimentally verified that lack of TFAP2A reduces HNSCC growth in vitro and that this effect is enhanced with cetuximab and a stronger effect is observed with JQ1, an inhibitor of alternative receptor tyrosine kinases. Corroborating our scRNA-seq observation, TFAP2A silencing does not affect cell migration, supporting the lack of interplay with the EMT pathway. Overall, our study shows that the immediate adaptive transcriptional and epigenetic changes induced by cetuximab include relevant pathways associated with acquired resistance. Although heterogeneous, these changes can be targeted by a multiple-target drug as JQ1 that in combination with cetuximab in the early stage of treatment present better efficacy in controlling tumor growth.
2020-05-04 | GSE137524 | GEO
Project description:10 cell lines (five cetuximab sensitive and five cetuximab resistant) were selected for gene copy number array analysis on the Affymetrix SNP 6.0 platform. 39 protein coding genes were amplified in cetuximab resistant cells and normal in sensitive cells, all present on genomic regions 11q22.1 or 5p13-15. Five genes were selected for quantitative PCR verification, namely, YAP1 and TRPC6 (11q22.1) and PDCD6, TPPP, and PTGER4 (5p13-15). An extended panel of totally 10 cetuximab resistant and 10 sensitive cell lines verified that YAP1 amplified cells are cetuximab resistant. YAP1 gene amplification was highly correlated to the YAP1 mRNA expression, which was significantly higher in cetuximab resistant cells than in sensitive. YAP1 downregulation resulted in increased cetuximab sensitivity in one of two cetuximab resistant cell lines investigated and growth inhibition in another. We conclude that YAP1 is a marker for cetuximab resistance in head and neck cancer. head and neck cancer cell lines with established cetuximab response were selected. 5 cetuximab resistant cell lines and 5 cetuximab sensitive cell lines were selected for gene genome wide gene copy number analysis on the Affymetrix SNP6.0 array
2012-12-01 | E-GEOD-36790 | biostudies-arrayexpress
Project description:10 cell lines (five cetuximab sensitive and five cetuximab resistant) were selected for gene copy number array analysis on the Affymetrix SNP 6.0 platform. 39 protein coding genes were amplified in cetuximab resistant cells and normal in sensitive cells, all present on genomic regions 11q22.1 or 5p13-15. Five genes were selected for quantitative PCR verification, namely, YAP1 and TRPC6 (11q22.1) and PDCD6, TPPP, and PTGER4 (5p13-15). An extended panel of totally 10 cetuximab resistant and 10 sensitive cell lines verified that YAP1 amplified cells are cetuximab resistant. YAP1 gene amplification was highly correlated to the YAP1 mRNA expression, which was significantly higher in cetuximab resistant cells than in sensitive. YAP1 downregulation resulted in increased cetuximab sensitivity in one of two cetuximab resistant cell lines investigated and growth inhibition in another. We conclude that YAP1 is a marker for cetuximab resistance in head and neck cancer.
2012-12-01 | GSE36790 | GEO