RNA-Seq shows the effect of EGFR-TKIs Dacomitinib on HaCaT cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1169841 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Dacomitinib treated HaCaT for 48 hours, Dacomitinib significantly increased Retinol metabolism pathway in HaCaT
2025-09-01 | GSE278965 | GEO
Project description:In this study, to investigate the underlying molecular mechanisms of how EGFR-TKIs resistance occurs in NSCLC, we examined gene expression using microarray technology on gefitinib-resistant NSCLC cells to obtain differentially expressed (DE) lncRNAs and mRNAs. Then we carried out KEGG enrichment analysis for DE-mRNAs and constructed the ceRNA regulatory network of DE-lncRNAs and DE-mRNAs. Our results revealed the downregulated lncRNA LINC01128 acted as ceRNA to decrease PTEN via sponging miR-25-3p, and then the signal reactions caused by the reduction of PTEN would activate PI3K/Akt signaling pathway, which may lead to the development of drug resistance to EGFR-TKIs in NSCLC. Our findings will provide a novel perspective for the underlying molecular mechanisms of EGFR-TKIs resistance in NSCLC. Besides, this research will help to develop new therapeutic targets for EGFR-TKIs resistance in NSCLC.
2022-01-14 | GSE193628 | GEO
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
Project description:Epidermal growth factor receptor (EGFR) mutations are leading oncogenic drivers in non-small cell lung cancer (NSCLC). Many third-generation EGFR tyrosine kinase inhibitors (TKIs) have been developed to target EGFR T790M and activating mutations. Osimertinib (AZD9291) was the first approved drug and is now the standard-of-care therapy for untreated EGFR-mutated NSCLC. Our team previously identified ASK120067, for which we have submitted a new drug application (NDA) in China. Although third-generation EGFR TKIs exhibit favorable antitumor effects in NSCLC treatment, acquired resistance with largely unexplored mechanisms still limits their long-term efficacy. In this study, we aimed to investigate the molecular mechanisms underlying resistance to EGFR TKIs and identify new therapeutic strategies for the treatment of NSCLC. Methods: Elevated expression of BCAT1 in EGFR TKI-resistant lung cancer cells was identified using stable isotope labeling by amino acids in cell culture (SILAC)-based proteomics analysis and verified with Western blotting and RT‒qPCR.
2023-07-14 | PXD043776 |
Project description:Lung cancer is the leading cause of cancer death. Mutations in the kinase domain of EGFR, a predominant driver oncogene, such as L858R missense mutation and a series of deletions spanning the conserved sequence 747LREA750, are associated with sensitivity to tyrosine kinase inhibitors (TKIs). However, patients receiving EGFR-TKIs (gefitinib and erlotinib) develop drug-resistance due to a secondary mutation at the gatekeeper residue (T790M) in about 50-60% of cases, urging for new drug development. Afatinib, a FDA approved second-generation EGFR-TKI that was developed to circumvent T790M-mediated resistance, has not been very effective in clinical trials. In this study, we performed a global phosphoproteomic screen to identify targets that undergo mutant EGFR-dependent tyrosine phosphorylation and their modulation by erlotinib or afatinib. We undertook stable isotope labeling of amino acids in cell culture (SILAC), phosphopeptide enrichment, and quantitative mass spectrometry to identify dynamic changes of phosphorylation downstream of mutant EGFRs in lung adenocarcinoma cells harboring L858R or L858R/T790M mutations and their modulation by erlotinib and afatinib inhibition. We identified and quantified 397, 429, 223, and 594 phosphotyrosine sites in H3255, 11-18,PC9, and H1975 cell lines that were grown in presence of FBS and in presence/absence of TKIs, respectively. These account for a total of 907 unique phospho-tyrosine sites in 496 proteins. Among them, 187 phosphotyrosine sites were found to be in 89 kinases, which may serve as intermediary regulatory kinases in EGFR signalling pathway. Further analysis indicated that in TKI-sensitive H3255 and 11-18 cells, there were 58/111 and 65/101 tyrosine sites that were hypophosphorylated in presence of erlotinib and afatinib, respectively. However, in TKI-resistant H1975 cells, 189 and 264 tyrosine sites were hypophosphorylated in presence of erlotinib and afatinib respectively, indicating that the afatinib-specific additional sites could be validated for identifying potentially new drug targets to counter TKI-resistance. Ingenuity pathway analysis (IPA) of proteins with altered phosphorylation sites demonstrated that several canonical pathways including ephrin receptor signalling and integrin signalling pathways were enriched, which may play important roles in cell growth and proliferation. However, upon EGF stimulation of serum starved H3255 cells in presence or absence of TKIs, 99 tyrosine sites that were hyperphosphorylated upon EGF stimulation were inhibited in presence of erlotinib or afatinib. But in H1975 cells treated with erlotinib, 48 of the above sites were either unchanged or were hyperphosphorylated. These sites include EGFR (Y1197/869/998), JAK1 (Y1034), FRK (Y497), GAB1 (Y657/689), MAPK1 (Y187), MAPK3 (Y204), MET (Y1252/1253). Furthermore, a total of 112 sites that were observed to be hypophosphorylated upon EGF stimulation in H1975 cells, were found to be hyperphosphorylated upon erlotinib inhibition. This could possibly be due to the activation of downstream phosphatases with EGF stimulation. We are now performing in-depth bioinformatic analysis and validation experiments using functional genomics to understand the role of targets of mutant EGFR signalling in lung cancer.
2017-03-29 | PXD004373 | Pride
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
Project description:Eliminating drug-tolerant persister (DTP) cells remain a significant challenge in overcoming resistance to tyrosine kinase inhibitors (TKIs) in EGFR-mutant lung adenocarcinoma. Utilizing single-cell RNA sequencing, we identify a novel RGS5+MYL9+ cancer associated fibroblasts (CAFs) subset. This subset is linked to TKI resistance and correlates with poorer prognosis. The RGS5+MYL9+ CAFs are spatially positioned close to DTP cells, a proximity facilitated by CCL11 recruitment from DTP cells. TKIs induced mitochondria ROS activates Rho GTPase 1 (Miro1) and RhoA of tumor cells, subsequently promoting the formation of tunneling nanotube connections with neighboring RGS5+MYL9+ CAFs. These CAFs play a protective role for DTP cells, aiding in the transfer of damaged mitochondria from tumor cells through these nanotubes. By employing the Rho kinase inhibitor Fasudil to block this transfer of damaged mitochondria, we observed a significant reduction in persistent tolerance to Osimertinib in a xenograft mouse model. Our study highlights the critical role of RGS5+MYL9+ CAFs in mediating resistance to EGFR-TKIs and suggests potential therapeutic strategies for overcoming this challenge.
2025-11-20 | GSE294147 | GEO
Project description:Non-small cell lung cancers (NSCLCs) harboring activating EGFR mutants show dramatic responses to EGFR TKIs, such as erlotinib and geffitinib. However, nearly all patients show relapse within 1 year after initial treatment. We used microarrays to detail global gene expression changes in EGFR mutant cells vs. WT cells responding to erlotinib. 4 EGFR mutant and 4 WT NSCLC cells were treated with or without erlotinib for 24 hr, followed by RNA extraction and hybridization on Affymetrix microarrays.
2014-05-16 | E-GEOD-57156 | biostudies-arrayexpress
Project description:To investigate the protective effect of Lycium barbarum polysaccharide-glycoprotein (LBP) in the radiation-induced HaCaT cell injury, We performed gene expression profiling analysis using data obtained from RNA-seq of HaCaT cells at 3h after radiation.
2024-06-01 | GSE218507 | GEO
Project description:Although tyrosine kinase inhibitors (TKIs) targeting Epidermal Growth Factor Receptor (EGFR) activating mutations have significantly improved outcomes in EGFR-mutant non-small cell lung cancer, resistance inevitably develops. Despite the heterogeneity of resistance mechanisms, many induce activation of MAPK signaling in the presence of EGFR-TKIs. ARAF gene amplification is identified as one such mechanism that activates MAPK signaling by directly interacting with RAS, yet its clinicopathologic characteristics remain poorly understood. We characterized five cases with ARAF amplification resistant to first- or second-generation EGFR-TKIs and screened an additional 48 re-biopsied specimens following resistance to Osimertinib. Among Osimertinib-resistant tumors, we identified four cases with ARAF amplification. Overall, these nine ARAF-amplified resistant tumors retained their original founder EGFR mutation and lacked secondary alterations. Furthermore, we identified two cases showing histologic transformation from lung adenocarcinoma to small cell lung cancer (SCLC). SCLC can be classified into four subtypes defined by transcriptional signatures driven by specific transcription factors. To estimate the subtypes of these resistant tumors, RNA sequencing analysis was performed in paired samples before and after treatment with EGFR-TKIs.
2024-10-30 | GSE274293 | GEO