Targeting COPA to enhance erdafitinib sensitivity in FGFR-altered bladder cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1168176 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30868301_1.fastq.gz | Fastqsanger.gz | |||
| SRR30868301_2.fastq.gz | Fastqsanger.gz | |||
| SRR30868302_1.fastq.gz | Fastqsanger.gz | |||
| SRR30868302_2.fastq.gz | Fastqsanger.gz | |||
| SRR30868303_1.fastq.gz | Fastqsanger.gz |
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Project description:Fibroblast growth factor receptor (FGFR) family aberrations are common in urothelial cancer. The FGFR tyrosine kinase inhibitor erdafitinib has been approved for locally advanced or metastatic urothelial cancer with FGFR2/3 alterations. Despite the initial efficacy of erdafitinib, resistance cannot be avoided. The molecular mechanism of erdafitinib resistance has not been well investigated. Here, we performed genome-wide CRISPR screen and identified coatomer protein complex subunit α (COPA) as a key target to enhance erdafitinib sensitivity. Functionally, the deficiency of COPA reduced the proliferation of FGFR-altered bladder cancer cells upon erdafitinib treatment. Mechanistically, COPA knockout increased LRPPRC protein degradation, leading to reduced ID3 mRNA stability in an m6A-dependent manner. Collectively, these findings reveal a novel mechanism of erdafitinib resistance, providing a potential therapeutic target for FGFR-altered bladder cancer.
2025-05-22 | GSE278672 | GEO
Project description:Mutations of the fibroblast growth factor receptor (FGFR) family members are frequently observed in metastatic bladder cancer. The development of erdafitinib, a pan-FGFR inhibitor, provides a significant therapeutic advance in bladder cancer, but resistance still limits its efficacy. In this study, we perform an unbiased whole-genome CRISPR-Cas9 synthetic lethal screen on FGFR-mutant bladder cancer cell lines treated with erdafitinib-targeted therapy and identify SRM as a critical contributor to erdafitinib resistance. In polyamine metabolism, SRM catalyzes the production of spermidine, which subsequently promotes the hypusination of eukaryotic translation factor 5A (eIF5A). Moreover, we demonstrate that hypusinated eIF5A (eIF5AHyp) facilitates the efficient translation of HMGA2, which in turn promotes EGFR expression. Notably, pharmacologic inhibition of SRM using MCHA enhances the efficacy of erdafitinib both in vitro and in vivo. Together, these results offer evidence of the synthetic lethality between SRM inhibition and erdafitinib, suggesting that combination treatment is a promising therapeutic strategy to overcome erdafitinib resistance for FGFR-mutant bladder cancer.
2024-12-31 | GSE276232 | GEO
Project description:Mutations of the fibroblast growth factor receptor (FGFR) family members are frequently observed in metastatic bladder cancer. The development of erdafitinib, a pan-FGFR inhibitor, provides a significant therapeutic advance in bladder cancer, but resistance still limits its efficacy. In this study, we perform an unbiased whole-genome CRISPR-Cas9 synthetic lethal screen on FGFR-mutant bladder cancer cell lines treated with erdafitinib-targeted therapy and identify SRM as a critical contributor to erdafitinib resistance. In polyamine metabolism, SRM catalyzes the production of spermidine, which subsequently promotes the hypusination of eukaryotic translation factor 5A (eIF5A). Moreover, we demonstrate that hypusinated eIF5A (eIF5AHyp) facilitates the efficient translation of HMGA2, which in turn promotes EGFR expression. Notably, pharmacologic inhibition of SRM using MCHA enhances the efficacy of erdafitinib both in vitro and in vivo. Together, these results offer evidence of the synthetic lethality between SRM inhibition and erdafitinib, suggesting that combination treatment is a promising therapeutic strategy to overcome erdafitinib resistance for FGFR-mutant bladder cancer.
2024-12-31 | GSE276411 | GEO
Project description:We first verified that erdafitinib is synergistic with quisinostat in vitro and confirmed that the combinational treatment can significantly enhance the inhibition of tumor growth and prolong the survival in vivo for bladder cancers with FGFR3 fusions. Next, in order to understand the underlying molecular mechanisms of this synergy, we performed RNA-seq analysis. We revealed that quisinostat can concomitantly inhibit FGFR signaling with erdafitinib by suppressing the translation of FGFR3 fusions. In addition, quisinostat can also sensitize bladder cancer cells to erdafitinib by downregulating HDGF, which is a second mechanism of the synergy independent of FGFR signaling.
2022-10-11 | GSE214814 | GEO
Project description:Background: Up to 40% of patients with estrogen receptor positive (ER+) breast cancer experience treatment resistance and disease recurrence, often caused by the upregulation of growth factor receptors. Understanding the mechanisms of resistance, and the identification of novel therapeutic targets is, therefore, of vital importance if breast cancer prognosis is to be further improved. Fibroblast growth factor receptor 1 (FGFR1) is a potential driver of endocrine resistance; however, clinically successful attempts at targeting FGFR1 activity in breast cancer are rare and may result from an inability to correctly identify patients that could benefit from such treatment. The identification of additional genes associated with an FGFR1-mediated mechanism of resistance will provide a more precise classification scheme for FGFR1-dependency in breast cancer. Methods: Live cell imaging and RNA sequencing of ER+ breast cancer cell lines (CAMA1, T47D, tamoxifen resistant T47D) were used to investigate FGFR1-dependency in breast cancer, mechanisms of endocrine resistance and the effects of treatment with tamoxifen and erdafitinib. An FGFR1-amplified ER+ breast cancer patient-derived xenograft (PDX) model was used to assess the effects of targeting FGFR1 in vivo. Gene expression analysis of human breast cancer from The Cancer Genome Atlas (TCGA) was used for clinical validation. Results: We evaluated the effects of targeting FGFR1 in ER+/HER2- breast cancer with aberrant FGFR1 amplification and/or overexpression. We found that the FGFR tyrosine kinase inhibitor (TKI) erdafitinib inhibited cell proliferation of FGFR1-amplified CAMA1 cells in vitro. Additionally, erdafitinib significantly enhanced the anti-proliferative effect of 4-hydroxytamoxifen (4-OHT) and its anti-tumor effect was also demonstrated in vivo. Further, we demonstrated that the proliferation of FGFR1-overexpressing tamoxifen-resistant T47D (TR-T47D) cells is dependent on FGFR1 activity. Moreover, these TR-T47D cells are re-sensitized to tamoxifen upon treatment with erdafitinib. Finally, we found that upregulation of genes related to epithelial-mesenchymal-transition (EMT) correlates with FGFR1 overexpression, and is reversed by FGFR inhibition. Conclusions: In this study we demonstrated that targeting FGFR1 in ER+/HER2- breast cancer with aberrant FGFR1 activity has the potential to inhibit tumor growth and to re-sensitize resistant tumors to tamoxifen. Furthermore, we identified a functional relationship between EMT, FGFR activity and endocrine resistance in breast tumorigenesis.
2022-08-01 | GSE200029 | GEO
Project description:Genome-wide synthetic lethal screen identifies SRM as a target that enhances erdafitinib efficacy in FGFR-mutant bladder cancer
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Project description:Genome-wide synthetic lethal Crispr screen identifies SRM as a target that enhances erdafitinib efficacy in FGFR-mutant bladder cancer
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Project description:Recently, FGFR1 has been found to be overexpressed in osteosarcoma and thus represents an important target for precision medicine. However, because targeted cancer therapy based on FGFR inhibitors has so far been less efficient than expected, a detailed understanding of the target is important. We have here applied proximity labelling of FGFR1 in an osteosarcoma cell line to identify determinants of FGFR1 activity. Many known FGFR interactors were identified (e.g. FRS2, PLC, RSK2, SHC4, SRC), but the data also suggested novel determinants. A strong hit in our screen was the tyrosine phosphatase PTPRG. We show that PTPRG and FGFR1 interact and colocalize at the plasma membrane where PTPRG directly dephosphorylates activated FGFR1. We further show that osteosarcoma cell lines depleted for PTPRG display increased FGFR activity and are hypersensitive to stimulation by FGF1. In addition, PTPRG depletion elevated cell growth and negatively affected the efficacy of FGFR kinase inhibitors. Thus, PTPRG may have future clinical relevance by being a predictor of outcome after FGFR inhibitor treatment.
2018-01-29 | PXD006157 | Pride
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:Epigenetic priming to enhance CAR-T cell cytotoxicity in bladder cancer
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