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

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. We perform RNA-seq on MGH-U3 cells to explore essential genes mediating erdafitinib resistance.