FGFR inhibition blocks NF-ĸB-dependent glucose metabolism and confers metabolic vulnerabilities in cholangiocarcinoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1009431 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26024302.fastq.gz | Fastqsanger.gz | |||
| SRR26024303.fastq.gz | Fastqsanger.gz | |||
| SRR26024304.fastq.gz | Fastqsanger.gz | |||
| SRR26024305.fastq.gz | Fastqsanger.gz | |||
| SRR26024306.fastq.gz | Fastqsanger.gz |
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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
Project description:This study explored the response to FGFR inhibition in FGFR2-fusion+ intrahepatic cholangiocarcinoma. We conducted phosphoproteomics experiments in a patient-derived FGFR2-driven ICC cell line model upon FGFR inhibition. Samples were treated with the FGFR inhibitor, Futibatinib/TAS120 (75 nM) for 4 or 24 hours or with DMSO vehicle.
The experiments were done using an Orbitrap Fusion Lumos mass spectrometer. Multiplexing was achieved using either TMT10/11 reagents and the SPS-MS3 method. Basic pH reversed-phase chromatography (bRPLC) was used for off-line pre-fractionation; 12 fractions were analyzed for proteome mappings (PMID: 26700037) and 24 fractions plus a phosphotyrosine-enriched sample for phosphoproteome mappings (PMID: 31606085). Phosphoproteome mappings were done using both HCD fragmentation with Orbitrap fragment ion detection and CID fragmentation with ion trap fragment ion detection (PMID: 29487189, PMID: 31606085).
Labeling scheme:
126: DMSO-1, ICC13-7 cells were treated with DMSO, replicate 1
127n: Futibatinib(TAS120)-4h-1, ICC13-7 cells were treated with Futibatinib (TAS120) for 4h, replicate 1
127c: Futibatinib(TAS120)-24h-1, ICC13-7 cells were treated with Futibatinib (TAS120) for 24h, replicate 1
128n: DMSO-2, ICC13-7 cells were treated with DMSO, replicate 2
128c: Futibatinib(TAS120)-4h-2, ICC13-7 cells were treated with Futibatinib (TAS120) for 4h, replicate 2
129n: Futibatinib(TAS120)-24h-2, ICC13-7 cells were treated with Futibatinib (TAS120) for 24h, replicate 2
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Project description:Dual targeting PPARα and NPC1L1 metabolic vulnerabilities blocks tumorigenesis
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Project description:<p>In this study, patients with advanced cancer across all histologies were enrolled in our IRB approved clinical sequencing program, called MI-ONCOSEQ, to go through an integrative sequencing which includes whole exome sequencing of the tumor and matched normal, and transcriptome sequencing. Four index cases were identified which harbor gene rearrangements of FGFR2 including two cholangiocarcinoma cases, a metastatic breast cancer case, and a metastatic prostate cancer case. After extending our assessment of FGFR rearrangements across multiple tumor cohorts, including TCGA, we identified FGFR gene fusions with intact kinase domains of FGFR1, FGFR2, or FGFR3 in cholangiocarcinoma, breast cancer, prostate cancer, lung squamous cell cancer, bladder cancer, thyroid cancer, oral cancer, glioblastoma, and head and neck squamous cell cancer. All FGFR fusion partners tested exhibit oligomerization capability, suggesting a shared mode of kinase activation. Overexpression of FGFR fusion proteins in vitro induced cell proliferation, and bladder cancer cell lines that harbors FGFR3 fusion proteins exhibited enhanced susceptibility to pharmacologic inhibition in vitro and in vivo. Due to the combinatorial possibilities of FGFR family fusion to a variety of oligomerization partners, clinical sequencing efforts which incorporate transcriptome analysis for gene fusions are poised to identify rare, targetable FGFR fusions across diverse cancer types.</p>
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Project description:Translocations involving FGFR2 gene fusions are common in cholangiocarcinoma and predict response to FGFR kinase inhibitors. However, response rates and durability of are limited due to the emergence of resistance, typically involving FGFR2 kinase domain mutations, and to sub-optimal dosing, relating to drug adverse effects. Here, we develop biparatopic antibodies targeting the FGFR2 extracellular domain (ECD), as candidate therapeutics. Biparatopic antibodies can overcome drawbacks of bivalent monospecific antibodies, which often show poor inhibitory or even agonist activity against oncogenic receptors. We show that oncogenic transformation by FGFR2 fusions requires an intact ECD. Moreover, by systematically generating biparatopic antibodies targeting distinct epitope pairs in FGFR2 ECD, we identified antibodies that effectively block signaling and malignant growth driven by FGFR2-fusions. Importantly, these antibodies demonstrate efficacy in vivo, synergy with FGFR inhibitors, and activity against FGFR2 fusions harboring kinase domain mutations. Thus, biparatopic antibodies may serve as new treatment options for patients with FGFR2-altered cholangiocarcinoma.
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Project description:Case Study of Acquired Resistance to FGFR Inhibition in Cholangiocarcinoma using Targeted DNA and RNA Sequencing
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Project description:Case Study of Acquired Resistance to FGFR Inhibition in Cholangiocarcinoma using Targeted DNA and RNA Sequencing
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Project description:<p>In this study, patients with advanced cancer across all histologies were enrolled in our IRB approved clinical sequencing program, called MI-ONCOSEQ, to go through an integrative sequencing which includes whole exome sequencing of the tumor and matched normal, and transcriptome sequencing. Four index cases were identified which harbor gene rearrangements of FGFR2 including two cholangiocarcinoma cases, a metastatic breast cancer case, and a metastatic prostate cancer case. After extending our assessment of FGFR rearrangements across multiple tumor cohorts, including TCGA, we identified FGFR gene fusions with intact kinase domains of FGFR1, FGFR2, or FGFR3 in cholangiocarcinoma, breast cancer, prostate cancer, lung squamous cell cancer, bladder cancer, thyroid cancer, oral cancer, glioblastoma, and head and neck squamous cell cancer. All FGFR fusion partners tested exhibit oligomerization capability, suggesting a shared mode of kinase activation. Overexpression of FGFR fusion proteins in vitro induced cell proliferation, and bladder cancer cell lines that harbors FGFR3 fusion proteins exhibited enhanced susceptibility to pharmacologic inhibition in vitro and in vivo. Due to the combinatorial possibilities of FGFR family fusion to a variety of oligomerization partners, clinical sequencing efforts which incorporate transcriptome analysis for gene fusions are poised to identify rare, targetable FGFR fusions across diverse cancer types.</p>
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Project description:Drugs that target specific gene alterations have proven beneficial in the treatment of cancer. Because cancer cells have multiple resistance mechanisms, it is important to understand the downstream pathways of the target genes and monitor the pharmacodynamic markers associated with therapeutic efficacy. We performed a transcriptome analysis to characterize the response of various cancer cell lines. We performed a transcriptome analysis to characterize the response of various cancer cell lines to a selective fibroblast growth factor receptor (FGFR) inhibitor (CH5183284/Debio 1347), a mitogen-activated protein kinase kinase (MEK) inhibitor, or a phosphoinositide 3-kinase (PI3K) inhibitor. We treated compounds for 24 hours and purified total RNA.
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