Notch3-dependent beta-catenin signaling mediates EGFR TKI drug persistence in EGFR mutant NSCLC
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ABSTRACT:
PROVIDER: PRJNA476332 | ENA |
REPOSITORIES: ENA
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Project description:EGFR tyrosine kinase inhibitors cause dramatic responses in EGFR-mutant lung cancer, but resistance universally develops. The involvement of β-catenin in EGFR TKI resistance has been previously reported however the precise mechanism by which β-catenin activation contributes to EGFR TKI resistance is not clear. Here, we show that EGFR inhibition results in the activation of β-catenin signaling in a Notch3-dependent manner, which facilitates the survival of a subset of cells that we call “adaptive persisters”. We previously reported that EGFR-TKI treatment rapidly activates Notch3, and here describe the physical association of Notch3 with β-catenin, leading to increased stability and activation of β-catenin. We demonstrate that the combination of EGFR-TKI and a β-catenin inhibitor inhibits the development of these adaptive persisters, decreases tumor burden, improves recurrence free survival, and overall survival in xenograft models. These results supports combined EGFR-TKI and β-catenin inhibition in patients with EGFR mutant lung cancer.
2018-08-31 | GSE115864 | GEO
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: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: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:Introduction: The clinical benefit of EGFR tyrosine kinase inhibitor (TKI) treatment in non-small cell lung cancer (NSCLC) patients with activating EGFR mutations is temporary, as virtually all patients develop acquired EGFR TKI resistance that occurs via diverse mechanisms. Here, we identified increased FGFR1 expression as such a resistance mechanism and using pathways analysis and drug combination testing we identified a novel combination treatment to control growth of these resistant tumors. Methods: Novel erlotinib-resistant NSCLC cell lines were generated and analyzed by mass spectrometry-based proteomics to identify altered pathways associated with erlotinib resistance. The altered pathways were further analyzed in gefitinib and osibenib resistant cell lines. Small molecule inhibitor combinations were used to block the altered pathways and investigate growth reduction in vitro and in two xenograft mouse models. FGFR1 mRNA levels were examined in pre- and (post?)- EGFR TKI treatment clinical tumor samples. Results: Proteomic analysis revealed increased expression of FGFR1 and AXL as well as increased Akt and ERK1/2 activation in a panel of novel erlotinib-resistant HCC827 cell lines. Combined treatment with erlotinib or osimertinib and a panel of small molecule inhibitors targeting AXL/MET, FGFRs, Akt, PI3K/mTOR, MEK or ERK1/2 showed that the most prominent re-sensitization to EGFR TKI occurred with the pan-FGFR inhibitor, PD173074. Interestingly, simultaneous blockade of components of the Akt pathway using specific Akt or dual PI3K-mTOR inhibitors combined with inhibitors targeting the FGFR family exhibited the most efficient growth inhibition of FGFR1 overexpressing EGFR TKI-resistant cell lines. Phosphorylation of proteins downstream of Akt, including PRAS40, FOXO and S6 ribosomal protein, were completely abrogated by PD173074 combined with the Akt inhibitor GSK2141795 . Combination treatment with PD173074 and an Akt inhibitor exhibited synergistic growth inhibition in vivo in two FGFR1 overexpressing NSCLC EGFR TKI-resistant animal models. Conclusion: The significant growth inhibition in vitro and in vivo observed with PD173074 combined with Akt compared to either drug alone imply that inhibition of several key targets may be beneficial in controlling erlotinib-resistant NSCLC. The complete abrogation of PRAS40, FOXO and S6 phosphorylations by PD173074 combined with an Akt inhibitor indicates that the Akt pathway is no longer active.
2021-07-08 | PXD011803 | Pride
Project description:EGFR tyrosine kinase inhibitors cause dramatic responses in EGFR-mutant lung cancer, but resistance universally develops. The involvement of ?-catenin in EGFR TKI resistance has been previously reported, however, the precise mechanism by which ?-catenin activation contributes to EGFR TKI resistance is not clear. Here, we show that EGFR inhibition results in the activation of ?-catenin signaling in a Notch3-dependent manner, which facilitates the survival of a subset of cells that we call "adaptive persisters". We previously reported that EGFR-TKI treatment rapidly activates Notch3, and here we describe the physical association of Notch3 with ?-catenin, leading to increased stability and activation of ?-catenin. We demonstrate that the combination of EGFR-TKI and a ?-catenin inhibitor inhibits the development of these adaptive persisters, decreases tumor burden, improves recurrence free survival, and overall survival in xenograft models. These results supports combined EGFR-TKI and ?-catenin inhibition in patients with EGFR mutant lung cancer.
| S-EPMC6090531 | biostudies-literature
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
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.
2023-05-31 | PXD034228 | JPOST Repository
Project description:The goal of this study was to compare the transcriptome (RNA-seq) of EGFR TKI sensitive NSCLC cells with that of cells with acquired resistance to erlotinib. HCC827 and HCC4006 cells were continuously cultured in erlotinib until erlotinib resistant (ER) variants emerged. All ER variants were negative for T790M. RNA from parental and ER cells was isolated for transcriptomic profiling. RNA-seq analysis reveals that EGFR TKI resistance is associated with a mesenchymal gene expression signature.
2020-09-03 | GSE121634 | GEO
Project description:Metabolic reprogramming is widely known as a hallmark of cancer cells to allow adaptation of cells to sustain survival signals. In the past decade, altered lipid metabolism has been recognized to be a property of malignant cells. In this report, we describe a novel oncogenic signaling pathway exclusively in tyrosine kinase inhibitor (TKI)-resistant epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC). EGFR mediates TKI-resistance through regulation of the fatty acid synthase (FASN), and inhibition of this pathway using the FASN inhibitor Orlistat, triggers cell death and reduces tumor sizes both in culture systems and in vivo. Together, data shown here provide compelling evidence that the fatty acid metabolism pathway is a candidate target for TKI-resistant NSCLC treatment.
2017-01-31 | GSE83666 | GEO