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YAP activation mediates acquired resistance to ALK inhibitor in ALK rearranged non–small cell lung cancer

ABSTRACT: To investigate a possible candidate for overcoming the acquired resistance to ALK-TKI, we established an in vitro model of acquired resistance to crizotinib (H3122-CR) by exposing EML4-ALK–positive H3122 lung cancer cells to increasing doses of crizotinib.

ORGANISM(S): Homo sapiens

PROVIDER: GSE117181 | GEO | 2019/12/31

REPOSITORIES: GEO

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Analysis of ALK TKI sensitive and ALK TKI resistant isogenic pairs of H3122 (EML4-ALK E13;A20) cells

Project description:Starting with H3122 cells, which harbor the EML4-ALK E13;A20 fusion and are known to be sensitive to ALK tyrosine kinase inhibitors, we generated isogenic pairs of ALK TKI sensitive and ALK TKI resistant cell lines using established methods (see Chmeliecki, J et al Science Trans Med 2011). We modeled resistance against the currently FDA approved ALK TKI, crizotinib (also called PF-1066). We also modeled resistance against a novel more potent ALK inhibitor, X-376 (ref: Lovly, CM et al Cancer Research 2011). We compared gene expression profiles between the 'parental' (ALK TKI sensitive) H3122 cells and the drug resistant cells (H3122 CR for Crizotinib resistant cells and H3122 XR for X-376 resistant cells).

2014-07-14 | GSE49508 | GEO

Gene expression profiles of an ALK-fusion driven cell line and its derivatives resistant to crizotinib alone or resistant to crizotinib plus afatinib

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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.

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Vulnerability of drug-resistant EML4-ALK rearranged lung cancer to transcriptional inhibition

Project description:A subset of lung adenocarcinomas is driven by the EML4-ALK translocation. Despite excellent initial responses in patients, acquired resistance to ALK inhibitors occurs. Exploring these mechanisms of resistance, we found that EML4-ALK cells resistant to ALK inhibitors are remarkably sensitive to THZ1, alvocidib or dinaciclib. These compounds robustly induce apoptosis through transcriptional inhibition and downregulation of anti-apoptotic genes. In conclusion, this study shows that THZ1, alvocidib or dinaciclib could be a therapeutic option for a subset of patients with acquired resistance to first, second and third-generation ALK inhibitors.

2019-12-15 | E-MTAB-8563 | biostudies-arrayexpress

Vulnerability of drug-resistant EML4-ALK rearranged lung cancer to transcriptional inhibition

2019-12-22 | E-MTAB-8590 | biostudies-arrayexpress

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

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2018-05-28 | GSE81261 | GEO

Deacetylation of miRNA-34a and miRNA-449 induces 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 (50mg/kg, 75mg/kg, 87.5mg/kg, 100mg/kg) to derive ceritinib-resistant tumors.

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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.

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ChIP-seq for identifying molecules 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 ChIP-seq analysis.

2018-05-28 | GSE81482 | GEO

Methylation profiling study by MBD-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 MBD-seq based methylation profiling.

2018-05-28 | GSE81483 | GEO

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