Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The structural dynamics of EGFR exon 19 mutants

ABSTRACT: Tyrosine kinase inhibitors (TKIs) are used to treat non-small cell lung cancers (NSCLC) driven by epidermal growth factor receptor (EGFR) mutations in the tyrosine kinase domain (TKD). TKI responses vary across tumors driven by the heterogeneous group of exon 19 deletions and mutations, but the molecular basis for these differences is not understood. We characterized the dynamics of the selected EGFR exon 19 mutants by HDX-MS to study the molecular basis of TKI sensitivity and tolerance.

INSTRUMENT(S): Synapt MS

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Yuko Tsutsui

LAB HEAD: Yuko Tsutsui

PROVIDER: PXD037355 | Pride | 2023-03-11

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	20210113_Del746_750_180sec.raw.zip	Raw
	20210113_Del746_750_manual_0sec.raw.zip	Raw
	20210113_Del746_750_manual_0sec_IA_final_peptide.csv	Csv
	20210114_Del746_750_0seconds.raw.zip	Raw
	20210114_Del746_750_10sec.raw.zip	Raw

Items per page:

1 - 5 of 253

Publications

Biochemical and structural basis for differential inhibitor sensitivity of EGFR with distinct exon 19 mutations.

van Alderwerelt van Rosenburgh Iris K IK Lu David M DM Grant Michael J MJ Stayrook Steven E SE Phadke Manali M Walther Zenta Z Goldberg Sarah B SB Politi Katerina K Lemmon Mark A MA Ashtekar Kumar D KD Tsutsui Yuko Y

Nature communications 20221110 1

Tyrosine kinase inhibitors (TKIs) are used to treat non-small cell lung cancers (NSCLC) driven by epidermal growth factor receptor (EGFR) mutations in the tyrosine kinase domain (TKD). TKI responses vary across tumors driven by the heterogeneous group of exon 19 deletions and mutations, but the molecular basis for these differences is not understood. Using purified TKDs, we compared kinetic properties of several exon 19 variants. Although unaltered for the second generation TKI afatinib, sensiti ...[more]

PMID: 36357385

Similar Datasets

Biochemical and Structural Basif for Differential Inhibitor Sensitivity of EGFR with Distinct Exon 19 Mutaions

Project description:Tyrosine kinase inhibitors (TKIs) are used to treat non-small cell lung cancers (NSCLC) driven by epidermal growth factor receptor (EGFR) mutations in the tyrosine kinase domain (TKD). We studied structural basis of differential TKI sensitivity among EGFR exon 19 mutants by HDX-MS.

2023-03-11 | PXD037374 | Pride

The strutural dynamics of EGFR Exon 19 mutants

Project description:Tyrosine kinase inhibtors are used to treat non-small cell lung cancers (NSCLC) driven by epidermal growth factor receptor (EGFR) mutations in the tyrosine kinase domain (TKD). We characterized the dynamics of purified EGFR exon 19 kinase domain mutants by HDX-MS with or withour erlotinib, one of the first-generation TKIs.

2023-03-11 | PXD037448 | Pride

Whole exome sequencing of EGFR-TKI naive and EGFR-TKI resistant lung adenocarcinoma samples

Project description:Whole exome sequencing was performed on set of 48 DNA samples obtained from 16 EGFR mutated NSCLC patients whose tumors progressed following EGFR-TKI treatment. The DNA samples included baseline biopsy, rebiopsy and blood from the same patient. By comparing the variants in rebiopsy tumors and baseline tumors we aim to understand the genomic alterations responsible for the development of EGFR-TKI resistance in NSCLC patients.

2022-02-11 | E-MTAB-11404 | biostudies-arrayexpress

Identification of clonal neoantigens derived from driver mutations in an EGFR mutated lung cancer patient benefitting from anti-PD-1

Project description:Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been recommended as the first line therapy for non-small cell lung cancer (NSCLC) with EGFR mutations. However, acquired resistance to EGFR-TKIs is inevitable. Although anti- programmed cell death 1 (PD-1)/PD-ligand (PD-L1) immunotherapies have achieved great clinical success as second-line treatment for many cancer types, the clinical efficacy of anti-PD-1/PD-L1 blockades in EGFR mutated NSCLC patients has been demonstrated to be obviously lower than those without EGFR mutations. Here, we reported an advanced NSCLC patient with exon 19 deletion and T790M EGFR mutation benefitting from anti-PD-1 blockade therapy after acquiring resistance to EGFR-TKI. We characterized the mutational landscape of the patient with next-generation sequencing (NGS), and successfully identified neoantigen-specific T cell clones derived from EGFR exon 19 deletion, TP53 A116T and DENND6B R398Q mutations. Our findings support the potential application of immune checkpoint blockades in NSCLC patients with acquired resistance to EGFR-TKIs in the context of specific clonal neoantigens with high immunogenicity. Personalized immunomodulatory therapy targeting these neoantigens should be explored for better clinical outcomes in EGFR mutant NSCLC patients.

2020-06-30 | GSE150972 | GEO

Differential mRNA expression analysis of EGFR-TKI-sensitive cells vs. EGFR-TKI-resistant cells

Project description:Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) resistance remains unknown. We determined gene expression profiling in EGFR-TKI-resistant cells using RNA-seq analysis

2021-04-18 | GSE172002 | GEO

Microarray expression profile of long noncoding RNAs in EGFR-TKI resistance of lung adenocarcinoma

Project description:Lung adenocarcinoma cells harboring epidermal growth factor receptor (EGFR) mutations are sensitive to EGFR tyrosine kinase inhibitors (TKIs). Prolonged cancer treatment will induce the development of acquired resistance to EGFR TKI. To gain insight into the molecular mechanisms of EGFR-TKIs resistance, we generate EGFR-TKI-resistant HCC827-8-1 cells to be analyzed by microarray with their parental HCC827cells. gefitinib resistant HCC827-8-1 cells with three replications; gefitinib-sensitive HCC827 cells with three replications

2016-08-23 | E-GEOD-74575 | biostudies-arrayexpress

Microarray expression profile of long noncoding RNAs in EGFR-TKI resistance of lung adenocarcinoma

2016-08-23 | GSE74575 | GEO

Novel EGFR-Mutant Mouse Models of Lung Adenocarcinoma Reveal Adaptive Immunity Requirement for Durable Osimertinib Response

Project description:Lung cancers bearing oncogenically-mutated EGFR represent a significant fraction of lung adenocarcinomas (LUADs) for which EGFR-targeting tyrosine kinase inhibitors (TKIs) provide a highly effective therapeutic approach. However, these lung cancers eventually acquire resistance and undergo progression within a characteristically broad treatment duration range. Our previous study of EGFR mutant lung cancer biopsies highlighted the positive association of a TKI-induced interferon g transcriptional response with increased time to treatment progression. Herein, we demonstrate that two additional gene expression signatures predictive of immunotherapy response also associate with longer duration of TKI treatment response, despite lack of efficacy of immunotherapy in EGFR mutant lung cancers. To test the hypothesis that host immunity contributes to the TKI response, we developed novel genetically-engineered mouse models of EGFR mutant lung cancer bearing exon 19 deletions (del19) or the L860R missense mutation. Both oncogenic EGFR mouse models developed multifocal LUADs from which transplantable cancer cell lines sensitive to the EGFR-specific TKIs, gefitinib and osimertinib, were derived. When propagated orthotopically in the left lungs of syngeneic C57BL/6 mice, deep and durable shrinkage of the cell line-derived tumors was observed in response to daily treatment with osimertinib. By contrast, orthotopic tumors propagated in immune deficient nu/nu mice exhibited modest tumor shrinkage followed by rapid progression on continuous osimertinib treatment. Osimertinib treatment significantly increased intratumoral CD3+ T cell content relative to diluent treatment. The findings provide strong evidence supporting the requirement for adaptive immunity in the durable therapeutic control of EGFR mutant lung cancer.

2022-11-09 | GSE217405 | GEO

Targeting 14-3-3ζ overcomes resistance to EGFR-TKIs in lung adenocarcinoma via BMP2/Smad/ID1 signaling

Project description:14-3-3ζ has been found to promote the proliferation, metastasis and chemoresistance of cancer cells in several cancers including lung adenocarcinoma; however, its significance in epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) resistance remains unknown. Our work uncovers a hitherto unappreciated role of 14-3-3ζ in EGFR-TKI resistance. We determined global gene expression profiling in EGFR-TKI-resistant H1975 cells using microarray analysis.

2020-09-30 | GSE156435 | GEO

Vitamin D3 Metabolites Demonstrate Prognostic Value in EGFR-Mutant Lung Adenocarcinoma and Can be Deployed to Oppose Acquired Therapeutic Resistance

Project description:EGFR tyrosine kinase inhibitors (EGFR TKIs) are the standard of care treatment for patients with EGFR-mutant lung adenocarcinoma (LUAD). Although initially effective, EGFR TKIs are not curative. Disease inevitably relapses due to acquired drug resistance. Here, we tested the ability of 1,25(OH)2D3 to promote epithelial differentiation and restore EGFR TKI sensitivity in models of EGFR TKI resistance that were associated with epithelial–mesenchymal transition (EMT).

2020-03-12 | GSE146850 | GEO