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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE241735 | GEO | 2024/03/20

REPOSITORIES: GEO

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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

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

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

2024-01-24 | MSV000093916 | MassIVE

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

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

Acquired FGFR and FGF alterations confer resistance to estrogen receptor (ER) targeted therapy in ER+ metastatic breast cancer

Project description:Beyond acquired mutations in the estrogen receptor (ER), mechanisms of resistance to ER-directed therapies in ER+ breast cancer have not been clearly defined. We conducted a genome-scale functional screen spanning 10,135 genes to investigate genes whose overexpression confer resistance to selective estrogen receptor degraders. Pathway analysis of candidate resistance genes demonstrated that the FGFR, ERBB, insulin receptor, and MAPK pathways represented key modalities of resistance. In parallel, we performed whole exome sequencing in paired pre-treatment and post-resistance biopsies from 60 patients with ER+ metastatic breast cancer who had developed resistance to ER-targeted therapy. The FGFR pathway was altered via FGFR1, FGFR2, or FGF3/FGF4 amplifications or FGFR2 mutations in 24 (40%) of the post-resistance biopsies. In 12 of the 24 post-resistance tumors exhibiting FGFR/FGF alterations, these alterations were not detected in the corresponding pre-treatment tumors, suggesting that they were acquired or enriched under the selective pressure of ER-directed therapy. In vitro experiments in ER+ breast cancer cells confirmed that FGFR/FGF alterations led to fulvestrant resistance as well as cross-resistance to the CDK4/6 inhibitor palbociclib, through activation of the MAPK pathway. The resistance phenotypes were reversed by FGFR inhibitors and, to a lesser extent, MEK inhibitors, suggesting potential treatment strategies.

2020-06-30 | GSE153509 | GEO

Identification of Targetable FGFR Gene Fusions in Diverse Cancers

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>

| phs000602 | dbGaP

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 fusion are of growing interest in brain tumors from a diagnostic and a theranostic point of view. It is encountered in rare and newly described tumor types. Here we performed a multiomics study on a series of 16 patients with FGFR2 fusion and show the correlation between histological, radiological and epigenetic features

Project description:FGFR fusion are of growing interest in brain tumors from a diagnostic and a theranostic point of view. It is encountered in rare and newly described tumor types. Here we performed a multiomics study on a series of 16 patients with FGFR2 fusion and show the correlation between histological, radiological and epigenetic features.

2024-03-31 | E-MTAB-13847 | biostudies-arrayexpress

Identification of Targetable FGFR Gene Fusions in Diverse Cancers

| phs000602.v1.p1 | EGA

FGF Receptor and Wnt-1 Signaling Cooperate in Mammary Tumorigenesis

Project description:The fibroblast growth factor pathway is known to cooperate with the highly oncogenic Wnt/ï¢-catenin pathway in mouse models of breast cancer. To investigate the mechanisms involved in this cooperativity, we utilized MMTV-driven transgenic mouse lines expressing a drug-inducible model for FGF Receptor signaling (iFGFR) crossed with the previously characterized MMTV-Wnt-1 mouse model. In these bigenic mice, both iFGFR1 and iFGFR2 activation resulted in a dramatic enhancement of mammary tumorigenesis. Tumor microarray analysis identified no transcriptional enhancement of Wnt/ï¢-catenin targets, however, identified a protein translational gene signature that also correlated with elevated FGFR1 and FGFR2 expression in several human breast cancer data sets. Additionally, iFGFR1 activation resulted in enhanced polysome recruitment and a marked increase in protein expression of several different Wnt/ï¢-catenin target oncogenes. Rapid FGFR-induced ERK activation and phosphorylation of key translation regulators was observed both in vivo in the transgenic mouse model, and in human breast cancer cell lines treated with exogenous FGF. These studies suggest that translational regulation is a key rate-limiting step required for oncogenic cooperativity between the Wnt and FGF pathways. reference X sample

2010-03-09 | E-GEOD-17916 | biostudies-arrayexpress

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