Affymetrix SNP array data for pulmonary adenocarcinomas with or without ALK fusion
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE41536 | GEO | 2013/10/10
SECONDARY ACCESSION(S): PRJNA177381
REPOSITORIES: GEO
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Project description:ALK fusion positive tumor constitutes a unique entitiy in lung adenocarcionmas. We compared the allelokaryotypes of ALK fusion positive and negative tumors with SNP array to get insight into the difference of genomic background of them. Copy number analysis with Affymetrix 250K SNP arrays of 35 ALK fusion positive and 95 ALK fusion negative lung adenocarcinomas was performed with annonymous references.
2013-10-10 | E-GEOD-41536 | biostudies-arrayexpress
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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.
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Project description:First line treatment for EML4-ALK fusion-positive lung cancer patient is the use of an ALK tyrosine kinase inhibitor (TKI), such as alectinib. While most patients initially respond to this therapy, many patients often develop relapse, and efficacious therapies for patients with relapse disease are limited. To study EML4-ALK fusion-positive lung cancer, novel murine lung cancer cell lines were generated from C57BL/6 mice using an intratracheally injected Adeno-virus that contains Cas9 and guide RNAs for the EML4-ALK translocation, which leads to the development of lung tumors. Cell lines were derived from these tumors. In an effort to better understand how cells respond to alectinib, we treated EML4-ALK-positive murine cell lines (EA1, EA2, and EA3 cells) in vitro for 1-7 days with either 100nM alectinib or DMSO-control. At each time point, RNA was isolated from each condition. RNA was submitted to RNA-seq. Differential analysis on the RNA-seq data was performed to determine and track gene changes over time between control and treated cells. These data will allow us to better develop novel therapeutics to use in conjunction with alectinib when treating EML4-ALK fusion-positive patients.
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Project description:Expression data of primary and metastasic tissues from ALK+ NSCLC patients (Anaplastic lymphoma kinase fusion positive non-small cell lung carcinoma)
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Project description:Identification of genes up-regulated in ALK-positive and EGFR/KRAS/ALK-negative lung adenocarcinomas. To elucidate molecular characteristics of lung adenocarcinomas (ADCs) with ALK mutations and those without EGFR, KRAS and ALK mutations, 226 primary lung ADCs of pathological stage I-II, examined for the status of EGFR, KRAS and ALK mutations, were subjected to genome-wide expression profiling, and genes up-regulated in lung ADCs with ALK mutations and those without EGFR, KRAS and ALK mutations were identified. One hundred and seventy-four genes, including ALK, were selected as being up-regulated specifically in 79 lung ADCs without EGFR and KRAS mutations. These 79 cases were divided into: 11 cases of ALK-positive ADCs, 36 cases of group A triple-negative ADCs, and 32 cases of group B triple-negative ADCs, by unsupervised clustering according to the expression of the 174 genes. In ALK-positive ADCs, 30 genes, including ALK itself and GRIN2A, were significantly overexpressed. Group A triple-negative ADC cases showed significantly worse prognoses for relapse and death than ADC cases with EGFR, KRAS or ALK mutations and group B triple-negative ADC cases. Nine genes were identified as being significantly up-regulated in group A triple-negative ADC cases and critical for predicting their prognosis. The nine genes included DEPDC1, which had been identified as a candidate diagnostic and therapeutic target in bladder and breast cancers. Genes discriminating this group of ADCs will be useful for selection of patients who will benefit from adjuvant chemotherapy after surgical resection of stage I-II triple-negative ADCs and also informative for the development of molecular targeting therapies for these patients. Expression profiles in of 226 lung adenocarcinomas (127 with EGFR mutation, 20 with KRAS mutation, 11 with EML4-ALK fusion and 68 triple negative cases).
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Project description:Using Fluorescence in situ hybridization (FISH), Comparative genomic hybridization on array (aCGH) and Targeted RNA sequencing (RNASeq), we observed a novel fusion of ALK with RPBJ that was amplified and immunohistochemically overexpressed in both the small sarcomatoid component of a chromophobe renal cell carcinoma (chRCC) and in its lymph node metastasis. The amplified RBPJ::ALK fusion was not detected in the chromophobe component of the primary tumour that harbored chRCC-typical losses of chromosomes 1, 2, 6, 10, 13 and 17. In contrast, the same mutations of PTEN, TP53 and TERT promoter were observed together in the three analyzed samples from chRCC, sarcomatoid component of the chRCC and metastasis.
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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).
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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 ChIP-seq analysis.
2018-05-28 | GSE81482 | GEO
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.
2018-05-28 | GSE97646 | GEO