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Deacetylation of miRNA-34a and miRNA-449 induces epithelial-mesenchymal transition and acquired resistance to ALK inhibitors

ABSTRACT: Treatment with ALK tyrosine kinase inhibitors often elicits profound initial antitumor responses in ALK fusion-positive patients with lung adenocarcinoma. However, patients invariably develop acquired resistance to ALK inhibitors. In this study, we aimed to identify molecular events that limit the durable response to ALK inhibition using genetic and epigenetic approaches. To identify novel mechanisms of acquired resistance to ALK inhibitors, we established in vivo and in vitro models of acquired resistance to ceritinib and crizotinib using H3122 and H2228 cells. For in vivo model, mice with established H3122-derived tumors were treated with four doses of ceritinib (50mg/kg, 75mg/kg, 87.5mg/kg, 100mg/kg) to derive ceritinib-resistant tumors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE97646 | GEO | 2018/05/28

REPOSITORIES: GEO

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Deacetylation of miRNA-34a and miRNA-449 induce epithelial-mesenchymal transition and acquired resistance to ALK inhibitors

Project description:Treatment with ALK tyrosine kinase inhibitors often elicits profound initial antitumor responses in ALK fusion-positive patients with lung adenocarcinoma. However, patients invariably develop acquired resistance to ALK inhibitors. In this study, we aimed to identify molecular events that limit the durable response to ALK inhibition using genetic and epigenetic approaches. To identify novel mechanisms of acquired resistance to ALK inhibitors, we established in vivo and in vitro models of acquired resistance to ceritinib and crizotinib using H3122 and H2228 cells. For in vivo model, mice with established H3122-derived tumors were treated with four doses of ceritinib (control, 75mg/kg, 87.5mg/kg, 100mg/kg) to derive ceritinib-resistant tumors.

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Methylation profiling study by MBD-seq for identifying genes associated with epithelial-mesenchymal transition and acquired resistance to ALK inhibitors

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ChIP-seq for identifying molecules associated with epithelial-mesenchymal transition and acquired resistance to ALK inhibitors

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Project description:Treatment with ALK tyrosine kinase inhibitors often elicits profound initial antitumor responses in ALK fusion-positive patients with lung adenocarcinoma. However, patients invariably develop acquired resistance to ALK inhibitors. In this study, we aimed to identify molecular events that limit the response to ALK inhibition using genetic and epigenetic approaches. To identify novel mechanisms of acquired resistance to ALK inhibitors, we established in vitro models of acquired resistance to ceritinib using H3122 cell. For in vitro model, H3122 parental cells, ceritinib-treated resistant cells, and non-resistant cells that combinely treated with certinib and panobinostat were used for small RNA-seq based miRNA expression profiling.

2018-05-28 | GSE81486 | GEO

Gene expression profiling study by RNA-seq for identifying genes associated with epithelial-mesenchymal transition and acquired resistance to ALK inhibitors

Project description:Treatment with ALK tyrosine kinase inhibitors often elicits profound initial antitumor responses in ALK fusion-positive patients with lung adenocarcinoma. However, patients invariably develop acquired resistance to ALK inhibitors. In this study, we aimed to identify molecular events that limit the response to ALK inhibition using genetic and epigenetic approaches. To identify novel mechanisms of acquired resistance to ALK inhibitors, we established in vitro models of acquired resistance to ceritinib using H3122 cell. For in vitro model, H3122 parental cells, ceritinib-treated resistant cells, and non-resistant cells that combinely treated with certinib and panobinostat were used for RNA-seq based gene expression profiling.

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Project description:Treatment with ALK tyrosine kinase inhibitors often elicits profound initial antitumor responses in ALK fusion-positive patients with lung adenocarcinoma. However, patients invariably develop acquired resistance to ALK inhibitors. In this study, we aimed to identify molecular events that limit the response to ALK inhibition using genetic and epigenetic approaches. To identify novel mechanisms of acquired resistance to ALK inhibitors, we established in vitro models of acquired resistance to ceritinib using H3122 cell. For in vitro model, H3122 parental cells, ceritinib-treated resistant cells, and non-resistant cells that combinely treated with certinib and panobinostat were used for RNA-seq based gene expression profiling.

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DNA methylation and gene expression changes during acquired resistance to ALK inhibitors (450k DNA methylation microarray)

Project description:To identify novel mechanisms of acquired resistance to ALK inhibitors, we established in vitro models of acquired resistance to ceritinib using H3122 cell. In this study, we examined genome-wide DNA methylation changes during acquired resistance to ceritinib. We also examined the heterogeneity of parental and resistant cells using single cell RNA--seq.

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DNA methylation and gene expression changes during acquired resistance to ALK inhibitors (scRNA-seq)

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Overcoming AXL Activation and Epithelial–Mesenchymal Transition is Critical in Conquering ALK-positive Non–Small Cell Lung Cancer

Project description:Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) induce a dramatic response in non–small cell lung cancer (NSCLC) patients with the ALK fusion gene. However, acquired resistance to ALK-TKIs in lung cancer cells remains an inevitable problem: ALK secondary mutations and bypass pathways have been reported as major resistance mechanisms. In this study, we aimed to discover a novel mechanism of acquired resistance to ALK-TKIs and a strategy to conquer ALK-positive lung cancer. We established three types of ALK-TKI (crizotinib, alectinib and ceritinib)–resistant H2228 non-small cell lung cancer cell lines by high exposure and stepwise methods. We found these cells showed a loss of ALK signaling, overexpressed AXL with epithelial–mesenchymal transition (EMT), and had cancer stem cell–like properties. Similarly, we demonstrated that TGF-β1 treated H2228 cells also showed AXL overexpression with EMT features and ALK-TKI–resistance. The AXL inhibitor, R428, or HSP90 inhibitor, ganetespib, were effective in reversing ALK-TKI–resistance and EMT changes in both ALK-TKI–resistant and TGF-β1–exposed H2228 cells. Progression-free survival of ALK-positive NSCLC patients with AXL overexpression was shorter than that of patients who underwent crizotinib therapy and showed low AXL expression. Thus, we found ALK signaling-independent AXL overexpression and EMT features were commonly involved in intrinsic and acquired resistance to first and second generation ALK-TKIs. This suggests AXL and HSP90 inhibitors may be promising therapeutic drugs to overcome tumor cells in ALK-positive NSCLC patients.

2017-02-17 | GSE94809 | GEO

Fibroblast growth factor receptor 3 overexpression mediates ALK inhibitor resistance in ALK-rearranged non-small cell lung cancer

Project description:The rearrangement of anaplastic lymphoma kinase (ALK) occurs in 3%-5% of patients with non-small cell lung cancer (NSCLC) and confers sensitivity to ALK-tyrosine kinase inhibitors (TKIs). For the treatment of patients with ALK-rearranged NSCLC, various additional ALK-TKIs have been developed. Ceritinib is a second-generation ALK-TKI and has shown great efficacy in the treatment of patients with both newly diagnosed and crizotinib, a first-generation ALK-TKI, refractory ALK-rearranged NSCLC. However, tumors can also develop ceritinib resistance. This may result from secondary ALK mutations, but other mechanisms responsible for this have not been fully elucidated. In this study, we explored the mechanisms of ceritinib resistance by establishing ceritinib-resistant, echinoderm microtubule-associated protein-like 4 (EML4)-ALK-positive H3122 cells and ceritinib-resistant patient-derived cells. We identified a mechanism of ceritinib resistance induced by bypass signals that is mediated by the overexpression and activation of fibroblast growth factor receptor 3 (FGFR3). FGFR3 knockdown by small hairpin RNA or treatment with FGFR inhibitors was found to resensitize the resistant cells to ceritinib in vitro and in vivo. FGFR ligands from either human serum or fetal bovine serum were able to activate FGFR3 and induce ceritinib resistance. A detailed analysis of ceritinib-resistant patient-derived specimens confirmed that tyrosine-protein kinase Met (cMET) amplification induces ceritinib resistance. Amplified cMET counter-activated EGFR and/or Her3, and induced ceritinib resistance. These results reveal multiple ceritinib resistance mechanisms and suggest that ceritinib resistance might be able to overcome by identifying precise resistance mechanisms.

2022-08-14 | GSE77764 | GEO

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