Analysis of differential gene expression in NSCLC cancer cell with or without EGFR-TKI resistance
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE262345 | GEO | 2025/03/22
REPOSITORIES: GEO
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Project description:Non-small cell lung cancer (NSCLC) lung adenocarcinoma (LUAD) is a leading cause of death worldwide. Activating mutations in the tyrosine kinase domain of the oncogene epidermal growth factor receptor (EGFR) are responsible for ~10-50% of all LUAD cases. Although EGFR tyrosine kinase inhibitors (TKIs) have been effective in prolonging NSCLC patient survival and quality of life, acquired resistance mechanisms and disease progression are inevitable. Contemporary second- and third-line treatments, such as immunotherapy, remain ineffective for these patients, presenting a clear and unmet need for alternative or adjuvant therapeutics for the treatment of mutant EGFR positive NSCLC. Here we show that an anti-EGFR aptamer (EGFRapt) decreases viability of NSCLC cell lines harboring the L858R ± T790M mutation in EGFR but not cell lines harboring wild-type or exon 19 deletions. In a humanized xenograft mouse model, EGFRapt decreased tumor burden compared to controls when delivered intratumorally over multiple doses. To elucidate the mechanism by which EGFRapt exerts these effects, we examined kinase-dependent and kinase-independent mechanisms and found that it is cell line dependent, either inhibiting cellular proliferation or inducing cell death. Post hoc transcriptomics analysis comparing EGFRapt to control aptamer or vehicle validated these findings and provided additional mechanistic insights. Overall, these data establish that EGFRapt has direct anti-cancer activity in mutant EGFR positive NSCLC via targetable mechanisms that are independent of existing approaches and provide a foundation for further development of nucleic acid-based therapies that target EGFR.
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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.
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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.
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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.
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Project description:The Epidermal Growth Factor Receptor (EGFR) regulates a diverse set of biological processes including cell growth, proliferation, and differentiation. Deregulation of the EGFR pathway has been implicated in a variety of human diseases including cancer. Gefitinib and erlotinib are tyrosine kinase inhibitors (TKIs) that have demonstrated clinical benefit for patients with Non-small cell lung cancer (NSCLC) and EGFR activating mutations. However, patients invariably acquire resistance to TKI treatment through a number of mechanisms. We utilized in vitro models of NSCLC with EGFR activating mutations and derived three isogenic cell lines with acquired resistance to gefitinib. We next studied genomewide mRNA expression in resistance and wild type cells and their effect in the reprogramming of pathways in lung cancer cell line models..
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Project description:Epidermal growth factor receptor (EGFR) inhibitors, as targeted therapies for non-small-cell lung cancer (NSCLC), have significantly enhanced patient survival and quality of life. However, despite these advancements, a significant proportion of patients exhibit resistance to EGFR inhibitors, limiting their overall treatment effectiveness. This study investigates the synergistic effects of combining Paeoniae Radix (PR) with the EGFR inhibitors erlotinib and gefitinib to overcome this resistance. The transcriptomic analysis of PR treatment revealed its potential to reverse the gene signature associated with resistance to EGFR inhibitors, as identified through analysis of a cell line database in EGFR mutant NSCLC. Combination treatment experiments validated that PR increased responsiveness to erlotinib and gefitinib in H1650 and H1975 NSCLC cells. By combining molecular experiments and transcriptome analysis, we found that PR may suppress resistance by modulating the Aurora B and apoptosis pathways. Notably, the combination therapy upregulated the apoptosis pathway and downregulated the Aurora B pathway more than single drug treatments. These results may contribute to the development of natural product-based combination therapeutic strategies to inhibit drug resistance in NSCLC.
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