Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA386287 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5528020_1.fastq.gz | Fastqsanger.gz | |||
| SRR5528020_2.fastq.gz | Fastqsanger.gz | |||
| SRR5528030_1.fastq.gz | Fastqsanger.gz | |||
| SRR5528030_2.fastq.gz | Fastqsanger.gz | |||
| SRR5528040_1.fastq.gz | Fastqsanger.gz |
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Project description:Integrated time course omics analysis distinguishes immediate therapeutic response from acquired resistance.
| PRJNA386291 | ENA
Project description:Integrated time course omics analysis distinguishes immediate therapeutic response from acquired resistance. (Methylation)
| PRJNA386303 | ENA
Project description:BACKGROUND: Targeted therapies specifically act by blocking the activity of proteins that are encoded by genes critical for tumorigenesis. However, most cancers acquire resistance and long-term disease remission is rarely observed. Understanding the time course of molecular changes responsible for the development of acquired resistance could enable optimization of patients treatment options. Clinically, acquired therapeutic resistance can only be studied at a single time point in resistant tumors. To determine the dynamics of these molecular changes, we obtained high throughput omics data weekly during the development of cetuximab resistance in a head and neck cancer in vitro model. RESULTS: An unsupervised algorithm, CoGAPS, was used to quantify the evolving transcriptional and epigenetic changes. Applying a PatternMarker statistic to the results from CoGAPS enabled novel heatmap-based visualization of the dynamics in these time course omics data. We demonstrate that transcriptional changes result from immediate therapeutic response or resistance, whereas epigenetic alterations only occur with resistance. Integrated analysis demonstrates delayed onset of changes in DNA methylation relative to transcription, suggesting that resistance is stabilized epigenetically. CONCLUSIONS: Genes with epigenetic alterations associated with resistance that have concordant expression changes are hypothesized to stabilize resistance. These genes include FGFR1, which was associated with EGFR inhibitor resistance previously. Thus, integrated omics analysis distinguishes the timing of molecular drivers of resistance. Our findings provide a relevant towards better understanding of the time course progression of changes resulting in acquired resistance to targeted therapies. This is an important contribution to the development of alternative treatment strategies that would introduce new drugs before the resistant phenotype develops.
2018-04-24 | GSE98813 | GEO
Project description:BACKGROUND: Targeted therapies specifically act by blocking the activity of proteins that are encoded by genes critical for tumorigenesis. However, most cancers acquire resistance and long-term disease remission is rarely observed. Understanding the time course of molecular changes responsible for the development of acquired resistance could enable optimization of patients treatment options. Clinically, acquired therapeutic resistance can only be studied at a single time point in resistant tumors. To determine the dynamics of these molecular changes, we obtained high throughput omics data weekly during the development of cetuximab resistance in a head and neck cancer in vitro model. RESULTS: An unsupervised algorithm, CoGAPS, was used to quantify the evolving transcriptional and epigenetic changes. Applying a PatternMarker statistic to the results from CoGAPS enabled novel heatmap-based visualization of the dynamics in these time course omics data. We demonstrate that transcriptional changes result from immediate therapeutic response or resistance, whereas epigenetic alterations only occur with resistance. Integrated analysis demonstrates delayed onset of changes in DNA methylation relative to transcription, suggesting that resistance is stabilized epigenetically. CONCLUSIONS: Genes with epigenetic alterations associated with resistance that have concordant expression changes are hypothesized to stabilize resistance. These genes include FGFR1, which was associated with EGFR inhibitor resistance previously. Thus, integrated omics analysis distinguishes the timing of molecular drivers of resistance. Our findings provide a relevant towards better understanding of the time course progression of changes resulting in acquired resistance to targeted therapies. This is an important contribution to the development of alternative treatment strategies that would introduce new drugs before the resistant phenotype develops.
2018-04-24 | GSE98812 | GEO
Project description:Therapeutic approaches to treat melanoma include small molecule drugs that target activating protein mutations in pro-growth signaling pathways like the MAPK pathway. While beneficial to the approximately 50% of patients with activating BRAFV600 mutation, mono- and combination therapy with MAPK inhibitors is ultimately associated with acquired resistance. To better characterize the mechanisms of MAPK inhibitor resistance in melanoma, we utilize patient-derived xenografts and apply proteogenomic approaches leveraging genomic, transcriptomic, and proteomic technologies that permit the identification of resistance-specific alterations and therapeutic vulnerabilities. A specific challenge for proteogenomic applications comes at the level of data curation to enable multi-omics data integration. Here, we present a proteogenomic approach that uses custom curated databases to identify unique resistance-specific alternations in melanoma PDX models of acquired MAPK inhibitor resistance. We demonstrate this approach with a NRASQ61L melanoma PDX model from which resistant tumors were developed following treatment with a MEK inhibitor. Our multi-omics strategy addresses current challenges in bioinformatics by leveraging development of custom curated proteogenomics databases derived from individual resistant melanoma that evolves following MEK inhibitor treatment and is scalable to comprehensively characterize acquired MAPK inhibitor resistance across patient-specific models and genomic subtypes of melanoma.
2024-05-10 | GSE266762 | GEO
Project description:Therapeutic approaches to treat melanoma include small molecule drugs that target activating protein mutations in pro-growth signaling pathways like the MAPK pathway. While beneficial to the approximately 50% of patients with activating BRAFV600 mutation, mono- and combination therapy with MAPK inhibitors is ultimately associated with acquired resistance. To better characterize the mechanisms of MAPK inhibitor resistance in melanoma, we utilize patient-derived xenografts and apply proteogenomic approaches leveraging genomic, transcriptomic, and proteomic technologies that permit the identification of resistance-specific alterations and therapeutic vulnerabilities. A specific challenge for proteogenomic applications comes at the level of data curation to enable multi-omics data integration. Here, we present a proteogenomic approach that uses custom curated databases to identify unique resistance-specific alternations in melanoma PDX models of acquired MAPK inhibitor resistance. We demonstrate this approach with a NRASQ61L melanoma PDX model from which resistant tumors were developed following treatment with a MEK inhibitor. Our multi-omics strategy addresses current challenges in bioinformatics by leveraging development of custom curated proteogenomics databases derived from individual resistant melanoma that evolves following MEK inhibitor treatment and is scalable to comprehensively characterize acquired MAPK inhibitor resistance across patient-specific models and genomic subtypes of melanoma.
2024-05-10 | GSE266735 | GEO
Project description:Although cancer immunotherapy with PD-(L)1 blockade is now routine treatment for patients with lung cancer, remarkably little is known about acquired resistance. We examined 1,201 patients with NSCLC treated with PD-(L)1 blockade to clinically characterize acquired resistance, finding it to be common (occurring in more than 60% of initial responders), with persistent but diminishing risk over time, and with distinct metastatic and survival patterns compared to primary resistance. To examine the molecular phenotype and potential mechanisms of acquired resistance, we performed whole transcriptome and exome tumor profiling in a subset of NSCLC patients (n=29) with acquired resistance. Systematic immunogenomic analysis revealed that tumors with acquired resistance differentially expressed features of inflammation and interferon (IFN) signalling. In particular, relapsed tumors could be separated into those with either upregulated or with stable expression of IFNγ response genes. Tumors with upregulated IFNγ response genes were associated with putative routes of resistance characterized by signatures of persistent IFN signaling, immune dysfunction, and mutations in antigen presentation genes. Transcriptomic profiling of cancer cells from multiple murine models of acquired resistance to PD-(L)1 blockade also showed evidence of high IFN-stimulated genes coupled to an altered or attenuated induced response after in vitro IFNγ treatment. In summary, we characterized clinical and molecular features of acquired resistance to PD-(L)1 blockade in NSCLC and found evidence of ongoing but altered IFN response. The persistently inflamed, rather than excluded or deserted, tumor microenvironment of acquired resistance informs therapeutic strategies to effectively reprogram and reverse acquired resistance.
2024-01-01 | GSE246922 | GEO
Project description:Endocrine therapies targeting the proliferative effect of 17β-estradiol (17βE2) through estrogen receptor α (ERα) are the most effective systemic treatment of ERα-positive breast cancer. However, most breast tumors initially responsive to these therapies develop resistance through a molecular mechanism that is not yet fully understood. The long-term estrogen-deprived (LTED) MCF7 cell model has been proposed to recapitulate acquired resistance to aromatase inhibitors (AIs) in postmenopausal women. To elucidate this resistance, genomic, transcriptomic and molecular data were integrated into the time course of MCF7-LTED adaptation. Dynamic and widespread genomic changes were observed, including amplification of the ESR1 locus consequently linked to an increase in ERα. Dynamic transcriptomic profiles were also observed that correlated significantly with genomic changes and were influenced by transcription factors known to be involved in acquired resistance or cell proliferation (e.g. IRF1 and E2F1, respectively) but, notably, not by canonical ERα transcriptional function. Consistently, at the molecular level, activation of growth factor signaling pathways by EGFR/ERBB/AKT and a switch from phospho-Ser118 (pS118)- to pS167-ERα were observed during MCF7-LTED adaptation. Evaluation of relevant clinical settings identified significant associations between MCF7-LTED and breast tumor transcriptome profiles that characterize ERα-negative status, early response to letrozole and recurrence after tamoxifen treatment. This study proposes a mechanism for acquired resistance to estrogen deprivation that is coordinated across biological levels and independent of canonical ERα function. LTED (long term estrogen deprived) cell line was generated from MCF-7 cells by long-term culture under estrogen deprivated conditions. And RNA samples were obtained after 3, 15, 30, 90, 120, 150 and 180 days.
2010-09-01 | E-GEOD-20361 | biostudies-arrayexpress
Project description:This experiment was done to detect the transcriptomic defects in the gcr1 null mutant, relative to an isogenic wild type, in the immediate response to glucose. Keywords: time course
2006-11-27 | GSE5575 | GEO
Project description:In spite of the advancements in targeted therapy for BRAFV600E-mutated metastatic colorectal cancer (mCRC), the development of resistance to BRAFV600E inhibition limits the response rate and durability of the treatment. Better understanding of the resistance mechanisms to BRAF inhibitors will facilitate the design of novel pharmacological strategies for BRAF-mutated mCRC. The aim of this study was to identify novel protein candidates involved in acquired resistance to BRAFV600E inhibitor vemurafenib in BRAFV600E-mutated colon cancer cells using an integrated proteomics approach. Our study suggests a role of ezrin in acquired resistance to vemurafenib in colon cancer and melanoma cells carrying BRAFV600E mutation and supports further pre-clinical and clinical studies to explore the benefits of combined BRAF inhibitors and actin-targeting drugs as a potential therapeutic approach for BRAFV600E-mutated cancers.
2023-08-29 | PXD042499 | Pride