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Longitudinal therapy monitoring of ALK-positive non-small cell lung cancer (copy number, cell-free DNA)

ABSTRACT: Clinical courses of non-small cell lung cancer patients with ALK rearrangements (ALK+ NSCLC) vary widely. We analyzed 271 longitudinal plasma samples from 73 patients with advanced ALK+ NSCLC treated with ALK tyrosine kinase inhibitors by combined hybrid-capture-based targeted sequencing (average 4,100x coverage) for mutation analysis and shallow whole genome sequencing (0.5x coverage) for global copy number profiling from cfDNA.

PROVIDER: EGAS00001004276 | EGA |

REPOSITORIES: EGA

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Gene expression-signatures for non-small cell lung cancer patients with different ALK mutational status.

Project description:To identify a plasma microRNA panel that could help to distinguish ALK positive with ALK negative NSCLC patients, plasma samples of 3 ALK-positive, 3 ALK-negative NSCLC, and 3 Healthy Subjects were selected for Agilent miRNA microarray analysis to detect differences in the expression levels of circulating miRNAs (n = 2568) between the above cohorts.

2017-02-07 | GSE94536 | GEO

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

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

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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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

Loss of Spindly sensitizes EML4-ALK v3 lung cancer cells to HSP90 inhibitors

Project description:Heat Shock Protein 90 inhibitors (HSP90i) have shown encouraging activity in EML4-ALK+ non-small cell lung cancer (NSCLC) patients but clinical responses have been heterogeneous. It has been suggested that distinct EML4-ALK variants may have a differential impact on the response to HSP90 inhibition. Here, we show that NSCLC cells harboring the most common EML4-ALK variant 1 (v1) or variant 3 (v3) are similarly sensitive to HSP90i. To discover new genetic alterations that could be involved in stratifying sensitivity, we performed a genome-wide CRISPR/Cas9 knockout screen and found that loss of Spindly increases the sensitivity of EML4-ALK v3, but not v1, NSCLC cells to low concentrations of HSP90i from three distinct chemical families. Upon loss of Spindly, prolonged exposure to low concentrations of HSP90i impairs chromosome congression and cellular fitness. Collectively, our data suggest that mutations leading to loss of Spindly in EML4-ALK v3 NSCLC patients may increase sensitivity to low doses of HSP90i.

2025-02-01 | GSE197655 | GEO

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

2011-06-03 | GSE25118 | 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.

2015-09-18 | GSE73167 | GEO

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

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

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