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Genome-wide synthetic lethal screen identifies SRM as a target that enhances erdafitinib efficacy in FGFR-mutant bladder cancer

ABSTRACT: We perform LC-MS to identify credential genes mediating erdafitinib resistacne

ORGANISM(S): Homo Sapiens

SUBMITTER: Guosong Jiang

PROVIDER: PXD055531 | iProX | Wed Sep 04 00:00:00 GMT+01:00 2024

REPOSITORIES: iProX

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A Genome-Wide Synthetic Lethal Screen Identifies Spermidine Synthase as a Target to Enhance Erdafitinib Efficacy in FGFR-Mutant Bladder Cancer.

Yu Yanchao Y Gao Xincheng X Zhao Huayuan H Sun Jiayin J Wang Miao M Xiong Xing X Li Junping J Huang Chao C Zhang Hui H Jiang Guosong G Xiao Xingyuan X

Cancer research 20250601 12

Mutations of the FGFR family members are frequently observed in metastatic bladder cancer. The development of erdafitinib, a pan-FGFR inhibitor, provided a significant therapeutic advance in bladder cancer, but resistance still limits its efficacy. In this study, we performed an unbiased whole-genome CRISPR-Cas9 synthetic lethal screen on FGFR-mutant bladder cancer cell lines treated with erdafitinib and identified spermidine synthase (SRM) as a critical contributor to erdafitinib resistance. Mo ...[more]

PMID: 40126530

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Genome-wide synthetic lethal screen identifies SRM as a target that enhances erdafitinib efficacy in FGFR-mutant bladder cancer

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.

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Genome-wide synthetic lethal Crispr screen identifies SRM as a target that enhances erdafitinib efficacy in FGFR-mutant bladder cancer

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Genome-wide synthetic lethal screen identifies SRM as a target that enhances erdafitinib efficacy in FGFR-mutant bladder cancer

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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Genome-wide synthetic lethal Crispr screen identifies SRM as a target that enhances erdafitinib efficacy in FGFR-mutant bladder cancer

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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A Genome-Wide Screen Identifies PDPK1 as a Target to Enhance the Efficacy of MEK1/2 Inhibitors in NRAS Mutant Melanoma.

Project description:Melanomas frequently harbor activating NRAS mutations. However, limited advance has been made in developing targeted therapy options for patients with NRAS mutant melanoma. MEK inhibitors (MEKi) show modest efficacy in the clinic and their actions need to be optimized. In this study, we performed a genome-wide CRISPR-Cas9-based screen and demonstrated that loss of phosphoinositide-dependent kinase-1 (PDPK1) enhances the efficacy of MEKi. The synergistic effects of PDPK1 loss and MEKi was validated in NRAS mutant melanoma cell lines using pharmacologic and molecular approaches. Combined PDPK1 inhibitors (PDPK1i) with MEKi suppressed NRAS mutant xenograft growth and induced gasdermin E-associated pyroptosis. In an immune-competent allograft model, PDPK1i+MEKi increased the ratio of intratumoral CD8+ T cells, delayed tumor growth, and prolonged survival; the combination treatment was less effective against tumors in immune-deficient mice. These data suggest PDPK1i+MEKi as an efficient immunostimulatory strategy against NRAS mutant melanoma.SignificanceTargeting PDPK1 stimulates antitumor immunity and sensitizes NRAS mutant melanoma to MEK inhibition, providing rationale for the clinical development of a combinatorial approach for treating patients with melanoma.

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Genome-Wide CRISPR Screen Identifies Multiple Synthetic Lethal Targets That Enhance KRAS (G12C) Inhibitor Efficacy

Project description:This SuperSeries is composed of the SubSeries listed below.

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Genome-wide CRISPR screen reveals the synthetic lethality between BCL2L1 inhibition and radiotherapy.

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Genome-Wide CRISPR Screen Identifies Multiple Synthetic Lethal Targets That Enhance KRAS (G12C) Inhibitor Efficacy [CRISPR]

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A genome-wide screen for identifying all regulators of a target gene.

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A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene.

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