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Microarray analysis of drug-tolerant cells in ALK-rearranged non-small cell lung cancer cell lines induced by ALK-TKIs

ABSTRACT: To investigate the molecular mechanisms underlying the emergence and maintenance of drug-tolerant (DT) cells in anaplastic lymphoma kinase (ALK)-rearranged lung cancer, we isolated DT cells from H2228 and A925L cells exposed to high doses of alectinib or lorlatinib for 9 days, and performed transcriptome analysis between parental and DT cells using a gene expression microarray.

ORGANISM(S): Homo sapiens

PROVIDER: GSE188406 | GEO | 2021/11/09

REPOSITORIES: GEO

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Alectinib-resistant NSCLC harboring EML4-ALK cells: Parental vs. Alectinib-resistant

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2015-09-18 | E-GEOD-73167 | biostudies-arrayexpress

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Effects of ALK inhibitory treatment with alectinib in glioblastoma cells

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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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