Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1155173 | ENA |
REPOSITORIES: ENA
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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:Docetaxel chemotherapy in metastatic prostate cancer offers only a modest survival benefit due to emerging resistance. To identify candidate therapeutic gene targets, we applied a murine prostate cancer orthograft model that recapitulates clinical invasive prostate cancer in a genome-wide CRISPR/Cas9 screen under docetaxel treatment pressure.
2020-10-07 | E-MTAB-9482 | biostudies-arrayexpress
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Project description:Genome-wide CRISPR-Cas9 knockout screen using TKOv1 sgRNA library performed in isogenic RBM10-proficient and RBM10-deficient HCC827 cells.
2024-03-01 | E-MTAB-13626 | biostudies-arrayexpress
Project description:Docetaxel chemotherapy in metastatic prostate cancer offers only a modest survival benefit due to emerging resistance. This experiment studies effect of TCEAL1 gene knock down with/without docetaxel treatment. The TCEAL1 gene was identified as the top candidate gene in vivo CRISPR/Cas9 screen.
2020-10-07 | E-MTAB-9484 | biostudies-arrayexpress
Project description:Genome-wide CRISPR-Cas9 knockout screen using TKOv1 sgRNA library was performed in isogenic RBM10-proficient and RBM10-deficient HCC827 cells.
2023-03-04 | E-MTAB-12724 | biostudies-arrayexpress
Project description:A CRISPR/Cas9 kinome knockout screen on gastric cancer cells
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Project description:To search for factors regulating paternally imprinted genes (PEGs), we performed a genome-wide loss-of-function CRISPR/Cas9 screen in haploid parthenogenetic ESCs. This by staining a pooled CRISPR library with a PEG10 antibody and next FACS-sorted for cells that presented de-novo PEG10 expression.
2021-10-21 | E-MTAB-11014 | biostudies-arrayexpress
Project description:Kynureninase is a member of a large family of catalytically diverse but structurally homologous pyridoxal 5'-phosphate (PLP) dependent enzymes known as the aspartate aminotransferase superfamily or alpha-family. The Homo sapiens and other eukaryotic constitutive kynureninases preferentially catalyze the hydrolytic cleavage of 3-hydroxy-l-kynurenine to produce 3-hydroxyanthranilate and l-alanine, while l-kynurenine is the substrate of many prokaryotic inducible kynureninases. The human enzyme was cloned with an N-terminal hexahistidine tag, expressed, and purified from a bacterial expression system using Ni metal ion affinity chromatography. Kinetic characterization of the recombinant enzyme reveals classic Michaelis-Menten behavior, with a Km of 28.3 +/- 1.9 microM and a specific activity of 1.75 micromol min-1 mg-1 for 3-hydroxy-dl-kynurenine. Crystals of recombinant kynureninase that diffracted to 2.0 A were obtained, and the atomic structure of the PLP-bound holoenzyme was determined by molecular replacement using the Pseudomonas fluorescens kynureninase structure (PDB entry 1qz9) as the phasing model. A structural superposition with the P. fluorescens kynureninase revealed that these two structures resemble the "open" and "closed" conformations of aspartate aminotransferase. The comparison illustrates the dynamic nature of these proteins' small domains and reveals a role for Arg-434 similar to its role in other AAT alpha-family members. Docking of 3-hydroxy-l-kynurenine into the human kynureninase active site suggests that Asn-333 and His-102 are involved in substrate binding and molecular discrimination between inducible and constitutive kynureninase substrates.
| S-EPMC2531291 | biostudies-literature