Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Evaluation of gene expression changes upon acquired resistance to anti-EGFR treatment in head and neck squamous cell carcinoma

ABSTRACT: We deciphered molecular mechanisms associated with acquired resistance to anti-EGFR targeted therapy in head and neck squamous cell carcinoma (HNSCC) by comparing gene expression profiles in cetuximab-sensitive and -resistant patient-derived xenograft (PDX) models of HNSCC. We generated and validated several HNSCC PDX models. Resistance mechanisms to anti-EGFR therapy were investigated in one of these PDX models (UCLHN04). First, sensitivity to cetuximab treatment was tested. This model showed high sensitivity to this drug. We induced acquired resistance to anti-EGFR therapy in this sensitive model by treating it chronically with anti-EGFR monoclonal antibody (cetuximab, 30 mg/kg/week) until resistance ensues. RNA-seq analysis was performed on samples coming from untreated and cetuximab-resistant PDX, revealing major changes of expression at the mRNA level.

ORGANISM(S): Homo sapiens

PROVIDER: GSE235417 | GEO | 2024/11/08

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Genomic characterization of intrinsic and acquired resistance to cetuximab in colorectal cancer patients

Project description:Anti-EGFR antibodies are effective in therapies for late-stage colorectal cancer (CRC); however, many tumours are unresponsive or develop resistance. We performed genomic analysis of intrinsic and acquired resistance to anti-EGFR therapy in prospectively collected tumour samples from 25 CRC patients receiving cetuximab (an EGFR inhibitor). Of 25 CRC patients, 13 displayed intrinsic resistance to cetuximab; 12 were intrinsically sensitive. We obtained six re-biopsy samples at acquired resistance from the intrinsically sensitive patients. NCOA4–RET and LMNA–NTRK1 fusions and NRG1 and GNAS amplifications were found in intrinsic-resistant patients. In cetuximab-sensitive patients, we found KRAS K117N and A146T mutations in addition to BRAF V600E, AKT1 E17K, PIK3CA E542K, and FGFR1 or ERBB2 amplifications. The comparison between baseline and acquired-resistant tumours revealed an extreme shift in variant allele frequency of somatic variants, suggesting that cetuximab exposure dramatically selected for rare resistant subclones that were initially undetectable. There was also an increase in epithelial-to-mesenchymal transition at acquired resistance, with a reduction in the immune infiltrate. Furthermore, characterization of an acquired-resistant, patient-derived cell line showed that PI3K/mTOR inhibition could rescue cetuximab resistance. Thus, we uncovered novel genomic alterations that elucidate the mechanisms of sensitivity and resistance to anti-EGFR therapy in metastatic CRC patients.

2019-09-21 | E-MTAB-8340 | biostudies-arrayexpress

Integrated single cell and bulk gene expression and ATAC-seq reveals heterogeneity and early changes in pathways associated with resistance to cetuximab in HNSCC sensitive cell lines (scRNA-Seq)

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

Integrated single cell and bulk gene expression and ATAC-seq reveals heterogeneity and early changes in pathways associated with resistance to cetuximab in HNSCC sensitive cell lines

2020-05-04 | GSE135604 | GEO

Secondary Resistance to Anti-EGFR Therapy by Transcriptional Reprogramming in Patient-Derived Colorectal Cancer Models (hipo B012)

Project description:The development of secondary resistance (SR) in metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (anti-EGFR) antibodies is not fully understood at the molecular level. Here we tested in vivo selection of anti-EGFR SR tumors in 2 CRC patient-derived xenograft (PDX) models as a strategy for a molecular dissection of SR mechanisms. We analyzed 21 KRAS, NRAS, BRAF, and PI3K wild-type CRC patient-derived xenograft (PDX) models for their anti-EGFR sensitivity. Furthermore, 31 anti-EGFR SR tumors were generated via chronic in vivo treatment with cetuximab. A multi-omics approach was employed to address molecular primary and secondary resistance mechanisms. Gene set enrichment analyses were used to uncover SR pathways. Targeted therapy of SR PDX models was applied to validate selected SR pathways.

| EGAS00001005320 | EGA

Gene expression changes associated with acquired resistance to anti-EGFR therapy (cetuximab) in colorectal cancer cells

Project description:Despite the implementation of personalized medicine, patients with metastatic CRC (mCRC) still have a dismal overall survival due to the frequent occurrence of acquired resistance mechanisms thereby leading to clinical relapse. Understanding molecular mechanisms that support acquired resistance to anti-EGFR targeted therapy in mCRC is therefore clinically relevant and key to improving patient outcomes. Here, we observe distinct metabolic changes between cetuximab-resistant CRC cell populations, with in particular an increased glycolytic activity in KRAS-mutant cetuximab-resistant LIM1215 but not in KRAS-amplified resistant DiFi cells. We show that cetuximab-resistant LIM1215 cells have the capacity to recycle glycolysis-derived lactate to sustain their growth capacity. This is associated with an upregulation of the lactate importer MCT1 at both transcript and protein levels. Pharmacological inhibition of MCT1, with AR-C155858, reduces the uptake and oxidation of lactate and impairs growth capacity in cetuximab-resistant LIM1215 cells. This study identifies MCT1-dependent lactate utilization as a clinically actionable, metabolic vulnerability to overcome KRAS-mutant-mediated acquired resistance to anti-EGFR therapy in CRC.

2024-07-02 | GSE262796 | GEO

The expression profile of Cetuximab resistance in head-and-neck squamous cell carcinoma cells.

Project description:Cetuximab (Erbitux) is an antibody drug against EGFR and commonly used in late stage HNSCC and metastatic colorectal cancer. The oncogenic mutation of certain genes are known to drive Cetuximab resistance such as K-RAS or b-RAF mutation. The aberrant activation of signaling pathways in the presence of Cetuximab treatment to overcome cellular stress contribute to acquired resistance to Cetuximab as well. To better understand the mechanisms and molecular patterns of Cetuximab resistant cells, the Cetuximab resistant cells are trained for examining the gene expression profile. The gene expression array is used for identify the molecular signature governing the Cetuximab resitance.

2017-03-02 | GSE63916 | GEO

Functional RNAi Screens Define Distinct Protein Kinase Vulnerabilities in EGFR-Dependent HNSCC Cell Lines

Project description:Cetuximab, an epidermal growth factor receptor (EGFR) inhibitory antibody, is an approved therapy for head and neck squamous cell carcinoma (HNSCC). Despite the EGFR dependency of HNSCC, cetuximab alone or combined with radio- or chemotherapy fails to yield long-term control or cures. Herein, we submitted EGFR-dependent HNSCC cell lines to RNAi-based functional genomics screens to identify, in an unbiased fashion, essential protein kinases for growth and survival as well as synthetic lethal targets for combined inhibition with EGFR inhibitors. MTOR and ERBB3 were identified as the highest ranking essential kinase hits. MTOR dependency was confirmed by distinct shRNAs and high sensitivity of the cell lines to AZD8055 while ERBB3 dependency was validated by shRNA-mediated silencing. Further, a synthetic lethal kinome shRNA screen with a pan-ERBB inhibitor, AZD8931, identified multiple components of the ERK MAPK pathway, consistent with ERK reactivation and/or incomplete ERK pathway inhibition in response to EGFR inhibitor monotherapy. As validation, distinct MEK inhibitors yielded synergistic growth inhibition when combined with the EGFR inhibitors, gefitinib and AZD8931. The findings identify ERBB3 and MTOR as important pharmacological vulnerabilities in HNSCC and support combining MEK and EGFR inhibitors to enhance efficacy of agents such as cetuximab.

2020-01-29 | GSE132788 | GEO

Gene expression signatures modulated by epidermal growth factor receptor activation and their relationship to cetuximab resistance in head and neck squamous cell carcinoma

Project description:Aberrant activation of signaling pathways controlled in normal epithelial cells by the epidermal growth factor receptor (EGFR) has been linked to cetuximab (a monoclonal antibody against EGFR) resistance in head and neck squamous cell carcinoma (HNSCC). To infer relevant and specific pathway activation downstream of EGFR from gene expression in HNSCC, we generated gene expression signatures using immortalized keratinocytes (HaCaT) subjected to either ligand stimulation or pharmacological inhibition of the signaling intermediaries PI-3-Kinase and MEK or transfected with EGFR, RELA/p65, or HRASVal12. The gene expression patterns that distinguished the various HaCaT variants and conditions were inferred using the Markov chain Monte Carlo (MCMC) matrix factorization algorithm Coordinated Gene Activity in Pattern Sets (CoGAPS). This approach inferred gene expression signatures with greater relevance to cell signaling pathway activation than the expression signatures inferred with standard linear models. Furthermore, the pathway signature generated using HaCaT-HRASVal12 further associated with the cetuximab treatment response in isogenic cetuximab-sensitive (UMSCC1) and -resistant (1CC8) cell lines. Our data suggest that the CoGAPS algorithm can generate gene expression signatures that are pertinent to downstream effects of receptor signaling pathway activation and potentially be useful in modeling resistance mechanisms to targeted therapies. 58 total RNA collected from HaCaT cell lines with combinations of the following experimental conditions: forced expression of EGFR, RELA/p65, and HRAS-VAL12D; grown in PBS, serum starve, and media stimulated with TNF or EGF; treated with gefitinib, LY294002, and U1026.

2012-05-22 | E-GEOD-32975 | biostudies-arrayexpress

An Inducible TGF-Î²2-TGFÎ²R Pathway Modulates the Sensitivity of HNSCC Cells to Tyrosine Kinase Inhibitors Targeting Dominant Receptor Tyrosine Kinases

Project description:The epidermal growth factor receptor (EGFR) is overexpressed in approximately 90% of head and neck squamous cell carcinomas (HNSCC), and molecularly targeted therapy against the EGFR with the monoclonal antibody cetuximab modestly increases overall survival in head and neck cancer patients. We hypothesize that co-signaling through additional pathways limits the efficacy of cetuximab and EGFR-specific tyrosine kinase inhibitors (TKIs) in the clinical treatment of HNSCC. Analysis of gene expression changes in HNSCC cell lines treated 4 days with TKIs targeting EGFR and/or fibroblast growth factor receptors (FGFRs) identified transforming growth factor beta 2 (TGF-Î²2) induction in the three cell lines tested. Measurement of TGF-Î²2 mRNA validated this observation and extended it to additional cell lines. Moreover, TGF-Î²2 mRNA was increased in primary patient HNSCC xenografts treated for 4 weeks with cetuximab, demonstrating in vivo relevance of these findings. Functional genomics analyses with shRNA libraries identified TGF-Î²2 and TGF-Î² receptors (TGFÎ²Rs) as synthetic lethal genes in the context of TKI treatment. Further, direct RNAi-mediated silencing of TGF-Î²2 inhibited cell growth, both alone and in combination with TKIs. Also, a pharmacological TGFÎ²RI inhibitor similarly inhibited basal growth and enhanced TKI efficacy. In summary, the studies support a TGF-Î²2-TGFÎ²R pathway as a TKI-inducible growth pathway in HNSCC that limits efficacy of EGFR-specific inhibitors. HNSCC cell lines treated 4 days with TKIs targeting EGFR and/or fibroblast growth factor receptors (FGFRs) identified transforming growth factor beta 2 (TGF-Î²2) induction in the three cell lines tested

2016-03-22 | E-GEOD-67500 | biostudies-arrayexpress

Single cell gene expression profile of patient-derived head and neck squamous carcinoma cells subjected to different treatments.

Project description:As other tumours, HNSCC are heterogenous, hence different cell populations within a given tumour may have different response towards treatment. Most of previous studies on HNSCC resistance towards treatment have been performed on “bulk” samples, which confound the influence of its heterogenous nature. In the recent years, single cell sequencing technologies have been developing rapidly and successfully applied to investigate numerous cancer response towards treatment. A recent scRNA-seq study on HNSCC cell lines confirmed the heterogenous response towards cetuximab. To further investigate both intrinsic and acquired resistance in HNSCC, we employed two primary cells modelling different responses towards selection with EGFR inhibitor, radiation, as well as a combination of EGFR inhibitor and radiation. These cell populations were studied using RAID technology, in which RNA and protein level were simultaneously quantified at a single cell resolution.

2022-09-28 | GSE214146 | GEO

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