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Next Generation Sequencing of EGFR-mutant non-small cell lung cancer (NSCLC) cells with tyrosine kinase inhibitor (TKI)-resistance

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE156054 | GEO | 2023/07/31

REPOSITORIES: GEO

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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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Next Generation Sequencing of EGFR-mutant non-small cell lung cancer (NSCLC) cells with tyrosine kinase inhibitor (TKI)-resistance

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