Histologic transformation induced by EGFR tyrosine kinase inhibitors
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1145888 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30172106_1.fastq.gz | Fastqsanger.gz | |||
| SRR30172106_2.fastq.gz | Fastqsanger.gz | |||
| SRR30172107_1.fastq.gz | Fastqsanger.gz | |||
| SRR30172107_2.fastq.gz | Fastqsanger.gz | |||
| SRR30172108_1.fastq.gz | Fastqsanger.gz |
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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
Project description:Histologic transformation to small cell lung cancer (SCLC) is an increasingly common resistance mechanism to EGFR tyrosine kinase inhibitors in EGFR mutant lung adenocarcinoma (LUAD) that is underdiagnosed in clinical practice due to the requirement for tissue biopsy. Early and accurate detection of transformed (t)SCLC has important prognostic and therapeutic implications. To address this unmet need, we first comprehensively profiled the epigenomes of metastatic lung tumors finding widespread epigenomic reprogramming during histologic transformation from LUAD to SCLC. We then utilized a novel approach for epigenomic profiling of cell-free DNA, which discriminated patients with EGFR mutant tSCLC from patients with EGFR mutant LUAD with greater than 90% accuracy. This first demonstration of the ability to accurately, and non-invasively, detect small cell transformation in patients with EGFR mutant LUAD through epigenomic cfDNA profiling is a critical step towards a new paradigm of diagnostic and therapeutic precision for patients with advanced lung cancer.
2024-06-20 | GSE269746 | GEO
Project description:Host-dependent Phenotypic Resistance to EGFR Tyrosine Kinase Inhibitors
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Project description:We showed that CD8+ T cell-dependent antitumor response was induced by an EGFR-tyrosine kinase inhibitor (TKI) against syngeneic Egfr-mutant NSCLC tumors and that the effect was further pronounced by the sequential dual blockade of PD-1 and vascular endothelial growth factor receptor 2 (VEGFR2).
2023-02-22 | GSE197260 | GEO
Project description:The clinical efficacy of EGFR kinase inhibitors gefitinib and erlotinib is limited by the development of drug resistance. The most common mechanism of drug resistance is the secondary EGFR T790M mutation. Strategies to overcome EGFR T790M mediated drug resistance include the use of mutant selective EGFR inhibitors, including WZ4002, or by the use of high concentrations of irreversible quinazoline EGFR inhibitors such as PF299804. In the current study we develop drug resistant versions of the EGFR mutant PC9 cell line which reproducibly develops EGFR T790M as a mechanism of drug resistance to gefitinib. Neither PF299804 resistant (PFR) or WZ4002 resistant (WZR) clones of PC9 harbor EGFR T790M. Instead, they demonstrate activated IGF1R signaling as a result of loss of expression of IGFBP3 and the IGF1R inhibitor, BMS 536924, restores EGFR inhibitor sensitivity. Intriguingly, prolonged exposure to either PF299804 or WZ4002 results in the emergence of a more drug resistant subclone which contains ERK activation. A MEK inhibitor, CI-1040, partially restores sensitivity to EGFR/IGF1R inhibitor combination. Moreover, an IGF1R or MEK inhibitor used in combination with either PF299804 or WZ4002 completely prevents the emergence of drug resistant clones in this model system. Our studies suggest that more effective means of inhibiting EGFR T790M will prevent the emergence of this common drug resistance mechanism in EGFR mutant NSCLC. However, multiple drug resistance mechanisms can still emerge. Preventing the emergence of drug resistance, by targeting pathways activated in resistant cancers before they emerge, may be a more effective clinical strategy. Total of three samples with duplicate or triplicate each were analyzed.
2012-10-01 | E-GEOD-38404 | 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
Project description:The clinical efficacy of EGFR kinase inhibitors gefitinib and erlotinib is limited by the development of drug resistance. The most common mechanism of drug resistance is the secondary EGFR T790M mutation. Strategies to overcome EGFR T790M mediated drug resistance include the use of mutant selective EGFR inhibitors, including WZ4002, or by the use of high concentrations of irreversible quinazoline EGFR inhibitors such as PF299804. In the current study we develop drug resistant versions of the EGFR mutant PC9 cell line which reproducibly develops EGFR T790M as a mechanism of drug resistance to gefitinib. Neither PF299804 resistant (PFR) or WZ4002 resistant (WZR) clones of PC9 harbor EGFR T790M. Instead, they demonstrate activated IGF1R signaling as a result of loss of expression of IGFBP3 and the IGF1R inhibitor, BMS 536924, restores EGFR inhibitor sensitivity. Intriguingly, prolonged exposure to either PF299804 or WZ4002 results in the emergence of a more drug resistant subclone which contains ERK activation. A MEK inhibitor, CI-1040, partially restores sensitivity to EGFR/IGF1R inhibitor combination. Moreover, an IGF1R or MEK inhibitor used in combination with either PF299804 or WZ4002 completely prevents the emergence of drug resistant clones in this model system. Our studies suggest that more effective means of inhibiting EGFR T790M will prevent the emergence of this common drug resistance mechanism in EGFR mutant NSCLC. However, multiple drug resistance mechanisms can still emerge. Preventing the emergence of drug resistance, by targeting pathways activated in resistant cancers before they emerge, may be a more effective clinical strategy.
2012-10-01 | GSE38404 | GEO
Project description:The clinical efficacy of EGFR kinase inhibitors is limited by the development of drug resistance. The irreversible EGFR kinase inhibitor WZ4002 is effective against the most common mechanism of drug resistance mediated by the EGFR T790M mutation. Here we show that in multiple complementary models harboring EGFR T790M, resistance to WZ4002 develops through aberrant activation of ERK signaling caused by either an amplification of MAPK1 or by downregulation of negative regulators of ERK signaling. Inhibition of MEK or ERK restores sensitivity to WZ4002, and the combination of WZ4002 and a MEK inhibitor prevents the emergence of drug resistance. The WZ4002 resistant MAPK1 amplified cells also demonstrate an increase both in EGFR internalization and a decrease in sensitivity to cytotoxic chemotherapy compared to the parental counterparts. Our findings provide insights into mechanisms of drug resistance to EGFR kinase inhibitors and highlight rational combination therapies that should be evaluated in clinical trials. Our study identifies ERK signaling as a mediator of resistance to irreversible pyrimidine EGFR inhibitors in EGFR T790M-bearing cancers. We further provide a therapeutic strategy to both treat and prevent the emergence of this resistance mechanism. To generate drug-resistant NCI-H1975 cell lines, non-small cell lung cancer (NSCLC) cells were exposed to increasing concentrations of WZ4002 similar to previously described methods. Individual clones from WZ4002-resistant (WZR) cells were isolated and confirmed to be drug resistant. Clone #6, designated as WZR6, was used in this study. For expression analysis, samples were prepared in triplicate from parental NCI-H1975 and NCI-H1975 WZR6 cells.
2012-10-01 | E-GEOD-37699 | biostudies-arrayexpress
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-β2) induction in the three cell lines tested. Measurement of TGF-β2 mRNA validated this observation and extended it to additional cell lines. Moreover, TGF-β2 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-β2 and TGF-β receptors (TGFβRs) as synthetic lethal genes in the context of TKI treatment. Further, direct RNAi-mediated silencing of TGF-β2 inhibited cell growth, both alone and in combination with TKIs. Also, a pharmacological TGFβRI inhibitor similarly inhibited basal growth and enhanced TKI efficacy. In summary, the studies support a TGF-β2-TGFβR 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-β2) induction in the three cell lines tested
2016-03-22 | E-GEOD-67500 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE37698: Reactivation of ERK signaling causes resistance to EGFR kinase inhibitors (SNP array) GSE37699: Aberrant ERK signaling causes resistance to EGFR kinase inhibitors Refer to individual Series
2012-10-01 | E-GEOD-37700 | biostudies-arrayexpress