Cancer Res. 2025 Mar 24.
Yanchao Yu,
Xincheng Gao,
Huayuan Zhao,
Jiayin Sun,
Miao Wang,
Xing Xiong,
Junping Li,
Chao Huang,
Hui Zhang,
Guosong Jiang,
Xingyuan Xiao.
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, 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.