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Regulation of gene expression in ALK inhibitor CH5424802-treated NCI-H2228 xenograft tumors

ABSTRACT: To clarify the downstream signal pathway of EML4-ALK in NSCLC, we performed Affymetrix GeneChip analysis using ALK inhibitor CH5424802-treated NCI-H2228 xenograft tumors, and comprehensively characterized the gene expression regulated by inhibition of activated ALK.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE25118 | GEO | 2011/06/03

SECONDARY ACCESSION(S): PRJNA134515

REPOSITORIES: GEO

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Regulation of gene expression in ALK inhibitor CH5424802-treated NCI-H2228 xenograft tumors

Project description:To clarify the downstream signal pathway of EML4-ALK in NSCLC, we performed Affymetrix GeneChip analysis using ALK inhibitor CH5424802-treated NCI-H2228 xenograft tumors, and comprehensively characterized the gene expression regulated by inhibition of activated ALK. Mice bearing NCI-H2228 cells were orally administered at dose of 0 (vehicle), 4 or 20 mg/kg of CH5424802, and the tumors were collected and lysed at 6 hours post-dose. Total RNA were extracted from xenograft tumors.

2011-06-03 | E-GEOD-25118 | biostudies-arrayexpress

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

Project description:Transcriptional profiling of NSCLC harboring EML4-ALK comparing parental H2228 cells with alectinib resistant H2228 cells.

2015-09-18 | GSE73167 | GEO

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

Project description:Transcriptional profiling of NSCLC harboring EML4-ALK comparing parental H2228 cells with alectinib resistant H2228 cells. Two-condition experiment, H2228 vs. H2228/CHR cells. Biological replicates: 1 parental replicates, 3 alectinib-resistant replicates.

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

RNA-seq of human NSCL cell lines with induced fusion genes; ALK-EML4-V1, ALK-EML4-V3, ALK-TFG, ALK-KIF5B

Project description:To characterize the effects of common ALK fusion genes, we performed a comprehensive RNA-Seq analysis of NL20 cells induced with ALK-EML4-V1, ALK-EML4-V3, ALK-TFG, ALK-KIF5B, using Doxycycline

2022-12-18 | E-MTAB-11304 | biostudies-arrayexpress

ALK fusion NSCLC oncogenes promote survival and inhibit NK cell responses via SERPINB4 expression

Project description:Anaplastic lymphoma kinase (ALK) fusion variants in non-small-cell-lung cancer (NSCLC) consist of numerous dimerising fusion partners, with the most common being EML4. Clinical data suggests that the degree of treatment benefit in response to ALK tyrosine kinase inhibitors (TKIs) differs among the variant present in the patient tumor. Therefore, a better understanding the oncogenic signaling networks driven by different ALK-fusion variants is important. Here, we developed highly controlled doxycycline-inducible cell models bearing four different ALK fusion proteins, namely EML4-ALK-V1, EML4-ALK-V3, KIF5B-ALK, and TFG-ALK, in the context of non-tumorigenic NL20 human bronchial epithelial cells. These were complimented by patient-derived NSCLC cell lines harboring either EML4-ALK-V1 or EML4-ALK-V3 fusions. RNAseq and phosphoproteomics analysis were employed to identify dysregulated genes and hyper/hypo-phosphorylated proteins associated with ALK fusion expression. Among ALK fusion induced responses, we noted a robust inflammatory signature that included up-regulation of the Serpin B4 serine protease inhibitor in both NL20-inducible cell models and ALK-positive NSCLC patient-derived cell lines. We show that STAT3 is a major transcriptional regulator of SERPINB4 downstream of ALK fusions, along with NF-B and AP1. The upregulation of SERPINB4 promotes survival of ALK fusion expressing cells and inhibits natural killer (NK) cell-mediated cytotoxicity. In conclusion, our study reveals a novel ALK downstream survival axis that regulates Serpin B4 expression and identifies a molecular target that has potential for therapeutic impact targeting the immune response together with ALK TKIs in NSCLC.

2023-02-16 | PXD035100 | Pride

EML4-ALK induces cellular senescence in mortal normal human cells and promotes anchorage-independent growth in hTERT-transduced normal human cells

Project description:Background: Chromosomal inversions involving anaplastic lymphoma kinase (ALK) and echinoderm microtubule associated protein like 4 (EML4) generate a fusion protein EML4-ALK in non-small cell lung cancer (NSCLC). The understanding of EML4-ALK function can be improved by a functional study using normal human cells. Methods: Here we for the first time conduct such study to examine the effects of EML4-ALK on cell proliferation, cellular senescence, DNA damage, gene expression profiles and transformed phenotypes. Results: The lentiviral expression of EML4-ALK in mortal, normal human fibroblasts caused, through its constitutive ALK kinase activity, an early induction of cellular senescence with accumulated DNA damage, upregulation of p16INK4A and p21WAF1, and senescence-associated -galactosidase (SA-β-gal) activity. In contrast, when EML4-ALK was expressed in normal human fibroblasts transduced with telomerase reverse transcriptase (hTERT), which is activated in the vast majority of NSCLC, the cells showed accelerated proliferation and acquired anchorage-independent growth ability in soft-agar medium, without accumulated DNA damage, chromosome aberration, nor p53 mutation. EML4-ALK induced the phosphorylation of STAT3 in both mortal and hTERT-transduced cells, but RNA sequencing analysis suggested that the different signaling pathways contributed to the different phenotypic outcomes in these cells. While EML4-ALK also induced anchorage-independent growth in hTERT-immortalized human bronchial epithelial cells in vitro, the expression of EML4-ALK alone did not cause detectable in vivo tumorigenicity in immunodeficient mice. Conclusions: Our data indicate that the expression of hTERT is critical for EML4-ALK to manifest its in vitro transforming activity in human cells. This study provides the isogenic pairs of human cells with and without EML4-ALK expression.

2021-01-20 | GSE165137 | GEO

Differential Chemoproteomics Reveals MARK2/3 as Cell Migration-Relevant Targets of the ALK Inhibitor Brigatinib

Project description:Metastasis poses a major challenge in cancer management, including EML4-ALK-rearranged non-small cell lung cancer (NSCLC). As cell migration is a critical step during metastasis, we assessed the anti-migratory activities of several clinical ALK inhibitors in NSCLC cells and observed differential anti-migratory capabilities despite similar ALK inhibition, with brigatinib displaying superior anti-migratory effects over other ALK inhibitors. Applying an unbiased in-situ mass spectrometry-based chemoproteomics approach, we determined the proteome-wide target profile of brigatinib in EML4-ALK+ NSCLC cells. Dose-dependent and cross-competitive chemoproteomics suggested MARK2 and MARK3 as relevant brigatinib kinase targets. Functional validation showed that combined pharmacological inhibition or genetic modulation of MARK2/3 inhibited cell migration. Consistently, brigatinib treatment induced inhibitory YAP1 phosphorylation downstream of MARK2/3. Collectively, our data suggest that brigatinib exhibits unusual cross-phenotype polypharmacology as despite similar efficacy for inhibiting EML4-ALK-dependent cell proliferation as other ALK inhibitors, it more effectively prevented migration of NSCLC cells due to co-targeting of MARK2/3.

2024-04-05 | PXD036716 | Pride

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

Expression data from EML4-ALK overexpression in HEK293 cell line and EML4-ALK knockdown in H2228 lung cancer cell line.

Project description:We demonstrate that EML4-ALK siRNAs significantly reduced cell viability in EML4-ALK postive lung cancer cell lines,while overexpression of EML4-ALK increased cell viability in HEK293 cells in vitro. The aim of this study was to analyze the EML4-ALK regulated gene expression in lung cancer.

2021-05-20 | GSE174772 | GEO

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

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