CD8+ T cell-1 dependent antitumor response boosted by dual blockade of PD-1 and VGFR2 following EGFR-tyrosine kinase inhibitors against lung cancer with Egfr mutation
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE197260 | GEO | 2023/02/22
REPOSITORIES: GEO
Similar Datasets
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
Project description:Purpose: The aim of this study is to compare the differentially expressed transcriptome of TKI resistance NSCLC cells and their parental cells Methods: mRNA profiles of the TKI-resistant NSCLC cells and their parental cells were generated by deep sequencing using Illumina HiSeq4000. Clean RNA-seq data was quantified and analyzed using the CLC genomics workbench software version 11.0 (Qiagen, Hilden, Germany). Results: In the current study, we established three EGFR-TKI-resistant cell lines and analyzed their expression profiles by RNA sequencing. We mapped about 30 million sequence reads per sample to the human genome (hg38) sequence and identified 21,463 transcripts in the parental and TKI-resistant NSCLC cells. Over 10% of the transcripts showed differential expression between the parental andTKI-resistant NSCLC cells, with a fold change ≥1.5 and p value <0.05. Transcriptome data analysis revealed the existence of significant overlaps and significant upregulation of epithelial-mesenchymal transition (EMT) pathway in the three cell lines with EGFR-TKI resistance. Conclusions: Our results showed that RNA-seq based transcriptome characterization offers a comprehensive and more accurate quantitative and qualitative evaluation of mRNA content within TKI-resistant NSCLC cells.
2023-07-31 | GSE156054 | GEO
Project description:Intratumoral heterogeneity in EGFR mutant NSCLC results in divergent resistance mechanisms in response to EGFR tyrosine kinase inhibition We used microarrays to investigate the gene expression underlying EGFR TKI resistance with a mesenchymal phenotype.
2016-06-04 | GSE69181 | GEO
Project description:Epidermal growth factor receptor (EGFR) harboring active mutations, Del19 and L858R, are most common oncogenic mutations in in non-small cell lung cancer (NSCLC) patients. The preferred treatment at first line is tyrosine kinase inhibitor (TKI) administration while the TKI-resistance usually develops because of acquiring the secondary EGFR T790M mutant. Protein-protein interactions (PPIs) constitute the signaling scaffold and thus aberrant PPIs ascribed to mutations often results in dysregulations of downstream signaling cascades. Affinity purification coupled mass spectrometry (AP-MS) was utilized to characterize the EGFR PPIs in four NSCLC cells which carry different EGFR subtypes representing as TKI-sensitive and -resistant models in this study. The EGFR interactomes of TKI-resistant NSCLC cells presented higher diversity of subcellular distribution as well as the hyperactive EGFR trafficking. Furthermore, gefitinib perturbation activated autophagy-mediated EGFR degradation in TKI-resistant NSCLC models and inhibiting autophagy process indeed reduced the TKI-resistance against gefitinib as cytotoxicity was significantly improved. Alternatively, gefitinib induced EGFR translocation toward cell periphery through Rab7 ubiquitination in TKI-sensitive models which may confer TKIs more chance to suppress EGFR activity. In brief, acquired T790M EGFR mutation rewired the EGFR inherent interactomes and thus guided EGFR moving toward distinct trafficking routes, EGFR recycling or autophagy-mediated degradation, in response to TKI insult in TKI-sensitive and -resistant NSCLC cells. These finding suggest that manipulation or combined autophagy inhibition may provide us a novel therapeutic strategy to manage TKI-resistance and tumor relapse in NSCLC.
| PXD034228 | JPOST Repository
Project description:In this study, we explored the mechanisms of hypoxia-induced EGFR TKI resistance in non-small cell lung cancer (NSCLC) harbored activating EGFR mutation. The NSCLC cell lines were exposed to normorxia or 1% oxygen for 4 weeks, and then we tested EGFR TKI sensitivity in normoxic and hypoxic NSCLC cell lines. In this microarray experiment, we used normoxic HCC827 and hypoxia-induced gefitinib resistant clones, C2-3 and C2-10. Those clones were selected with gefitinib treatment after the HCC827 were exposed to 1% oxygen for 4 weeks, and the HCC827 C2-3 and C2-10 clones were selected at random for this study.
2020-12-19 | E-MTAB-9452 | biostudies-arrayexpress
Project description:EGFR-mutated non-small cell lung cancers bear hallmarks including sensitivity to EGFR inhibitors, and low proliferation, and increased MET. However, the biology of EGFR dependence is still poorly understood. Using a training cohort of chemo-naive lung adenocarcinomas, we have developed a 72-gene signature that predicts (i) EGFR mutation status in four independent datasets; (ii) sensitivity to erlotinib in vitro; and (iii) improved survival, even in the wild-type EGFR subgroup. The signature includes differences associated with enhanced receptor tyrosine kinase (RTK) signaling, such as increased expression of endocytosis-related genes, decreased phosphatase levels, decreased expression of proliferation-related genes, increased folate receptor-1 (FOLR1) (a determinant of pemetrexed response), and higher levels of MACC1 (which we identify as a regulator of MET in EGFR-mutant NSCLC). Those observations provide evidence that the EGFR-mutant phenotype is associated with alterations in the cellular machinery that links the EGFR and MET pathways and create a permissive environment for RTK signaling. We have developed a gene expression signature that predicts (i) EGFR mutation in chemo-naive and, to a lesser extent, in chemo-refractory NSCLC patients; (ii) EGFR TKI response in vitro; and (iii) survival in wild-type EGFR patients. The signature also identifies novel features of EGFR mutant NSCLC including increased levels of endocytosis-related genes and MACC1, which appears be an EGFR mutant associated regulator of MET. Gene expression profiles were measured in 124 core biopsies from patients with refractory non-small cell lung cancer in the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial. We used the BATTLE dataset to test an EGFR-mutation gene expression signature trained in chemo-naive lung adenocarcinoma. The signature was computed as an index, called EGFR index.
2014-06-01 | E-GEOD-31852 | biostudies-arrayexpress
Project description:Aberrant overexpression or activation of EGFR drives the development of non-small cell lung cancer (NSCLC) and acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) by secondary EGFR mutations or c-MET amplification/activation remains as a major hurdle for NSCLC treatment. We previously identified WDR4 as a substrate adaptor of Cullin 4 ubiquitin ligase and an association of WDR4 high expression with poor prognosis of lung cancer. Here, using an unbiased ubiquitylome analysis, we uncover PTPN23, a component of the ESCRT complex, as a substrate of WDR4- based ubiquitin ligase. WDR4-mediated PTPN23 ubiquitination leads to its proteasomal degradation, thereby suppressing lysosome trafficking and degradation of wild type EGFR, EGFR mutant, and c-MET. Through this mechanism, WDR4 sustains EGFR and c-MET signaling to promote NSCLC proliferation, migration, invasion, stemness, and metastasis. Clinically, PTPN23 is downregulated in lung cancer and its low expression correlates with WDR4 high expression and poor prognosis. Targeting WDR4-mediated PTPN23 ubiquitination by a peptide that competes with PTPN23 for binding WDR4 promotes EGFR and c-MET degradation to block the growth and progression of EGFR TKI-resistant NSCLC. These findings identify a central role of WDR4/PTPN23 axis in EGFR and c-MET trafficking and a potential therapeutic target for treating EGFR TKI-resistant NSCLC.
2023-10-09 | PXD025361 | Pride
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). 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.
2023-03-11 | PXD037355 | Pride
Project description:The study was designed to identify the molecular changes that occur in EGFR mutant NSCLCs that become resistant to TKI by transforming to SCLC. Tyrosine kinase inhibitors (TKIs) are effective treatments for non-small cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, they do not lead to cures, and, on average, relapse occurs after one year of continuous treatment. In a subset of patients, a fundamental histological transformation from NSCLC to small cell lung cancer (SCLC) is observed in the resistant cancers, but the molecular changes associated with this transformation remain unknown. Analysis of a cohort of tumor samples and cell lines derived from resistant EGFR mutant patients with SCLC transformation revealed that RB is lost in 100% of these cases, but rarely in those that remain NSCLC. Global changes in gene expression, including increased neuroendocrine marker expression and absence of EGFR expression, are observed in cancers that transformed to SCLC. Consistent with their genetic and epigenetic similarities to classical SCLC, cell lines derived from resistant EGFR mutant SCLC biopsies are substantially more sensitive to ABT-263 treatment compared to those derived from resistant EGFR mutant NSCLCs. Together, these findings suggest that despite developing initially as EGFR mutant adenocarcinomas, this subset of resistant cancers ultimately take on many of the molecular and phenotypic characteristics of classical SCLC. Overall, we completed array CGH analysis on 4 tumor specimens from EGFR mutant, TKI-resistant patients. Three of these samples had transformed to SCLC and one remained NSCLC.
2015-01-30 | E-GEOD-64765 | biostudies-arrayexpress
Project description:Introduction: Overcoming of acquired resistance to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) is an intractable obstacle for many clinical oncologists. The mechanisms of resistance to EGFR-TKIs are very complex. Long non-coding RNAs (lncRNAs) may play an important role in cancer development and metastasis. However, the biological process between lncRNAs and drug resistance to EGFR mutated lung cancer largely unknown. Methods: Osimertinib and afatinib-resistant EGFR-mutated lung cancer cells were established using by a stepwise method. Microarray analysis of non-coding and coding RNAs was performed using parental and resistant EGFR-mutant NSCLC cells. Results: Microarray analysis was evaluated by bioinformatics analysis through medical-industrial collaboration. CRNDE and DGCR5 lncRNAs were highly expressed in EGFR-TKIs-resistant cells. CRNDE binds to eIF4A3 protein, down-regulates eIF4A3 and MUC1 expression, and down-regulates p-EGFR expression. CRNDE inhibition activated the eIF4A3/MUC1/EGFR signaling pathway and apoptotic activity and restored sensitivity to EGFR-TKIs. Conclusions: We identified lncRNA CRNDE associated with resistance to EGFR-TKIs in EGFR-mutant NSCLC cells. CRNDE may be a novel therapeutic target for EGFR mutant NSCLC patients.
2021-04-28 | GSE163913 | GEO