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Expression data from human endometrial cancer cell line AN3-CA treated with 300 nM AZD4547

ABSTRACT: AZD4547,pan-FGFR inhibitor, have been reported to have profound therapeutic effects on FGFR-deregulated cancers. AN3-CA is one of endometrial cancer cell lines harbouring FGFR2 mutants. AZD4547 showed a potent antiprolierative effect on AN3-CA cells. we used microarray to investigate transcriptome-wide change in gene expression followinig 300 nM AZD4547 treatment to explain the chemotherapeutic effect. compound treatment with or without ligand stimulus.

ORGANISM(S): Homo sapiens

SUBMITTER: yeonui Kwak

PROVIDER: E-GEOD-61481 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Expression data from human endometrial cancer cell line AN3-CA treated with 300 nM AZD4547

Project description:AZD4547,pan-FGFR inhibitor, have been reported to have profound therapeutic effects on FGFR-deregulated cancers. AN3-CA is one of endometrial cancer cell lines harbouring FGFR2 mutants. AZD4547 showed a potent antiprolierative effect on AN3-CA cells. we used microarray to investigate transcriptome-wide change in gene expression followinig 300 nM AZD4547 treatment to explain the chemotherapeutic effect.

2015-09-17 | GSE61481 | GEO

Phosphoproteomics of truncated FGFR2, a clinically actionable oncogene in multiple cancers

Project description:Somatic hotspot mutations and structural amplifications and fusions affecting fibroblast growth factor receptor 2 (FGFR2) occur in multiple cancer types. However, clinical responses to FGFR inhibitors (FGFRi) have remained variable, emphasizing a need to better understand which FGFR2 alterations are oncogenic and targetable. Here we applied transposon-based screening and tumor modelling in mice to uncover truncation of exon (E) 18 of Fgfr2 as a potent driver mutation. Human oncogenomic datasets revealed a diverse set of FGFR2 alterations, including rearrangements (REs), E1-E17 partial amplifications, and E18 nonsense and frameshift mutations, each causing transcription of E18-truncated FGFR2 (FGFR2deltaE18). Somatic modelling in mice and human tumor cell lines using a compendium of FGFR2deltaE18 and full-length variants identified FGFR2deltaE18-truncation as potent single-driver alteration in cancer. Here we show the phosphoproteomic landscape of FGFR2 variants in murine epithelial cell (MEC) lines and mouse tumors. Global (STY) phosphoproteomics using IMAC and phosphotyrosine phosphoproteomics using pTyr IP’s are combined with DIA protein expression data to uncover oncogenic signaling of clinically-relevant FGFR2 variants.

2022-06-06 | PXD031711 | Pride

RNA-seq of FGFR2 fusion+ ICC cell lines (ICC21 and ICC10-6) treated with Infigratinib or/and Afatinib against untreated control

Project description:Genomic alterations that activate Fibroblast Growth Factor Receptor 2 (FGFR2) are common in intrahepatic cholangiocarcinoma (ICC), a deadly bile duct malignancy. FGFR kinase inhibitors (FGFRi) have shown promising efficacy against FGFR2+ ICC in clinical trials, leading to the regulatory approval of the ATP-competitive FGFR inhibitors, pemigatinib and infigratinib (BGJ398), for this subset of patients who failed standard treatment . However, the objective response rate (ORR) for each FGFR inhibitor (FGFRi) studied to date in FGFR2+ ICC is <45% and disease progression invariably arises within ~6-12 months. By employing high-throughput drug screens and signaling studies, we identified signaling feedback via the EGFR pathway as a major mediator of adaptive resistance to FGFR kinase inhibition in a set of patient-derived ICC models. To further gain insights into the synergistic effects of the EGFR/FGFR combination and address the mechanisms underlying the survival pathway reactivation, we performed RNA sequencing in our FGFR-driven ICC models (ICC21 and ICC10-6). For these studies, we treated FGFR2 fusion+ ICC cell lines ICC21/ICC10-6 with four conditions (DMSO/Infigratinib/Afatinib/Combo) for 4 hours followed by RNA sequencing.

2024-03-21 | E-MTAB-11324 | biostudies-arrayexpress

Expression Profiles of E11.5 Mouse Optic Fissure

Project description:Mice that are mutant for both Fgfr1 and Fgfr2 specifically in the developing retina develop coloboma. To analyze the transcripts that are affected by defective FGF signaling, we micro-dissected the optic fissure region from the control and FGFR condtional mutant mice and did microarray analysis. E11.5 control and Six3Cre+; Fgfr1fx/fx;Fgfr2 fx/fx optic fissures are dissected using laser-assisted micro-dissection microscope, RNAs are extracted and labelled and hybridyzed to chips

2012-10-02 | E-GEOD-41260 | biostudies-arrayexpress

In vitro expression in FGFR inhibitor sensitive and resistant cell lines

Project description:The challenge of developing effective pharmacodynamic biomarkers for pre-clinical and clinical testing of FGFR signalling inhibition is significant. Assays that rely on the measurement of phospho-protein epitopes can be limited by the availability of effective antibody detection reagents. Transcript profiling enables accurate quantification of many biomarkers and a broader representation of pathway modulation. To identify dynamic transcript biomarkers of FGFR signalling inhibition by AZD4547, a potent inhibitor of FGF receptor 1, 2 and 3, a gene expression profiling study was performed in FGFR2 amplified drug sensitive tumour cell lines.

2016-08-25 | E-MTAB-4749 | biostudies-arrayexpress

The developing lens transcriptome depends upon a counterbalance of Fgfr2- and Pten-regulated downstream signaling and transcription factor targets

Project description:FGFR signaling plays important roles in development and disease pathogenesis. FGFR activation initiates phosphorylation-driven signaling cascades, most notably the RAS-RAF-MEK-ERK cascade and the PI3K-AKT cascade. PTEN antagonizes FGFR signaling by reducing both AKT and ERK activation. Lenses lacking FGFR2 exhibit lower levels of ERK and AKT phosphorylation accompanied by abnormally small lenses, widespread apoptosis, and defective fiber cell differentiation. In contrast, simultaneous deletion of both Fgfr2 and Pten restores ERK and AKT activation levels as well as lens size, cell survival and several aspects of fiber cell differentiation. A transcriptomic analysis of mouse lenses lacking Fgfr2, Pten or both Fgfr2 and Pten revealed molecular mechanisms that might explain how FGFR2 and PTEN signaling interact during development. The FGFR2-deficient lens transcriptome suggested an overall loss of fiber cell identity with deregulated expression of 1,448 genes, nearly 60% of which returned to normal expression levels in lenses lacking both Fgfr2 and Pten. A specific set of parameters based on expression levels in each genotype identified 68 high priority candidate genes. The homeobox transcription factor, NKX6-1, encoded by one of these genes, had at least one binding motif in the putative promoters of 53 of these 68 genes. Furthermore, NKX6-1 activated the expression of the high priority candidate Rasgrp1, a RAS-activating guanine nucleotide exchange factor. Together, these data suggest a novel regulatory module in which NKX6-1 activates the expression of Rasgrp1 to restore the balance of ERK and AKT activation in the absence of both FGFR2 and PTEN.

2020-02-28 | GSE132945 | GEO

FGFR inhibition blocks NF-ĸB-dependent glucose metabolism and confers metabolic vulnerabilities in cholangiocarcinoma

Project description:Genomic alterations that activate FGFR2 are common in intrahepatic cholangiocarcinoma (ICC) and confer sensitivity to treatment with FGFR inhibitors. However, the depth and duration of responses are often limited. Elucidating the FGFR2-driven oncogenic program and the adaptions to FGFR inhibition is needed to gain insight into the biology of these tumors and inform future therapeutic development. Here, we conducted transcriptomic analysis of patient-derived models to define the pathways that fuel tumor growth downstream of oncogenic FGFR2 signaling in ICC and to uncover compensatory mechanisms associated with pathway inhibition. For these studies, we performed RNA sequencing in our FGFR-driven ICC models, including cell line ICC13-7 , PDX MG69 and MG212. We treated ICC13-7 with DMSO or 75 nM Futibatinib for 4/12/24 hours, MG69 with vehicle or Futibatinib for 14 days and MG212 with vehicle or Pemigatinib for 11 days followed by RNA sequencing. In addition, ICC13-7 cells were transfected with siScramble and siRELA and followed by RNA sequencing.

2024-03-20 | GSE241735 | GEO

Azotobacter vinelandii CA strain:CA

Project description:Azotobacter vinelandii CA strain:CA Genome sequencing

| PRJNA186698 | ENA

Unraveling the Mechanisms of Sensitivity to Anti-FGF Therapies in Imatinib-Resistant Gastrointestinal Stromal Tumors (GIST) Lacking Secondary KIT Mutations

Project description:Acquired resistance of gastrointestinal stromal tumors (GISTs) to imatinib mesylate (IM) is one of the most critical challenges in GIST therapy. Here we show that a long-term culture of GIST T-1 cells with IM induces clonal heterogeneity resulting in the appearance of cancer cells exhibiting activation of the FGFR-signaling pathway which was associated with KIT loss. The first one was due to the overexpression of FGFR1/2 and increased production of FGF-2 ligand. These events maintained GIST resistance to IM and rendered these GIST cells highly sensitive to all types of pan-FGFR-inhibitors used in the current study. Knockout of FGFR2 in this GIST subclone significantly attenuated pro-apoptotic and anti-proliferative activities of infigratinib (BGJ 398) both in vitro and in vivo, thereby suggesting the activation of FGFR-signaling pathway via FGFR2-mediated axis as the predominant molecular mechanism in these GIST cells. Collectively, the extended inhibition of KIT-signaling in GISTs induces clonal heterogeneity of cancer cells and might change the tumor’s sensitivity to FGFR-inhibitors due to selection of cancer cells with an FGFR-overactivated pathway.

2023-11-09 | GSE247170 | GEO

Differential responses to kinase inhibition in FGFR2-addicted triple negative breast cancer cells: a quantitative phosphoproteomics study

Project description:Fibroblast Growth Factor (FGF) dependent signalling is frequently activated in cancer by a variety of different mechanisms. However, the downstream signal transduction pathways involved are poorly characterised. Here a quantitative differential phosphoproteomics approach, SILAC, is applied to identify FGF-regulated phosphorylation events in two triple- negative breast tumour cell lines, MFM223 and SUM52PE, that exhibit amplified expression of FGF receptor 2 (FGFR2) and are dependent on continued FGFR2 signalling for cell viability. Comparative Gene Ontology proteome analysis revealed that SUM52PE cells were enriched in proteins associated with cell metabolism and MFM223 cells enriched in proteins associated with cell adhesion and migration. FGFR2 inhibition by SU5402 impacts a significant fraction of the observed phosphoproteome of these cells. This study expands the known landscape of FGF signalling and identifies many new targets for functional investigation. FGF signalling pathways are found to be flexible in architecture as both shared, and divergent, responses to inhibition of FGFR2 kinase activity in the canonical RAF/MAPK/ERK/RSK and PI3K/AKT/PDK/mTOR/S6K pathways are identified. Inhibition of phosphorylation-dependent negative-feedback pathways is observed, defining mechanisms of intrinsic resistance to FGFR2 inhibition. These findings have implications for the therapeutic application of FGFR inhibitors as they identify both common and divergent responses in cells harbouring the same genetic lesion and pathways of drug resistance.

2020-05-20 | PXD016777 | Pride

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