ArticleCancer research2025
A Genome-Wide Synthetic Lethal Screen Identifies Spermidine Synthase as a Target to Enhance Erdafitinib Efficacy in FGFR-Mutant Bladder Cancer.
Article in Cancer research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Uncovering pan-cancer signatures of chemoresistance.Genome medicine · 2026Article
- Steroidogenesis is associated with bladder cancer progression via reprogramming the metabolic landscape of the tumor immune microenvironment.Discover oncology · 2026Article
- Synthetic lethality in cancer: mechanism exploration and therapeutic applications.Cell communication and signaling : CCS · 2026Review
- Synthetic lethality in cancer therapy: Mechanisms, models and clinical translation for overcoming therapeutic resistance.Clinical and translational medicine · 2026Review
- SRM Represents a Novel Prognosis Biomarker and Correlates With Inflammation and Immune Infiltration in Hepatocellular Carcinoma.Mediators of inflammation · 2026Article
- Polyamine metabolism related gene index prediction of prognosis and immunotherapy response in breast cancer.Frontiers in oncology · 2025Article
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Authors and funding
11 authors.
Funding
Abstract
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. Moreover, hypusinated eIF5A, catalyzed by SRM-mediated spermidine production, facilitated the efficient translation of HMGA2, which in turn promoted the expression of EGFR. Notably, pharmacologic inhibition of SRM enhanced the efficacy of erdafitinib both in vitro and in vivo. Together, these results offer evidence that targeting SRM could attenuate the translation of HMGA2 and subsequently reduce EGFR transcription, thus enhancing the sensitivity of FGFR-mutant bladder cancer cells to erdafitinib treatment. SIGNIFICANCE: Combined inhibition of polyamine metabolism and FGFR is a promising therapeutic strategy to overcome erdafitinib resistance and improve treatment for patients with FGFR-mutant bladder cancer.
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Registered trials
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