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Updated: Jul 9, 2026
A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
A Genome-Wide Synthetic Lethal Screen Identifies Spermidine Synthase as a Target to Enhance Erdafitinib Efficacy in
Yanchao Yu1, Xincheng Gao1, Huayuan Zhao1
1Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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.
Insights
Targeting spermidine synthase (SRM) overcomes erdafitinib resistance in fibroblast growth factor receptor (FGFR)-mutant bladder cancer. Inhibiting SRM reduces HMGA2 translation and EGFR expression, enhancing treatment efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Fibroblast growth factor receptor (FGFR) mutations are common in metastatic bladder cancer.
- Erdafitinib, a pan-FGFR inhibitor, shows therapeutic promise but faces resistance challenges.
Purpose of the Study:
- To identify mechanisms of erdafitinib resistance in FGFR-mutant bladder cancer.
- To explore novel therapeutic strategies targeting resistance pathways.
Main Methods:
- Whole-genome CRISPR-Cas9 synthetic lethal screening of FGFR-mutant bladder cancer cell lines.
- Assessment of erdafitinib efficacy with and without spermidine synthase (SRM) inhibition.
- In vitro and in vivo validation of identified resistance mechanisms.
Main Results:
- Spermidine synthase (SRM) was identified as a key mediator of erdafitinib resistance.
- SRM promotes HMGA2 translation via hypusinated eIF5A, leading to increased EGFR expression.
- Pharmacologic inhibition of SRM enhanced erdafitinib efficacy in preclinical models.
Conclusions:
- Targeting SRM can overcome erdafitinib resistance in FGFR-mutant bladder cancer.
- Inhibiting SRM attenuates HMGA2 translation and EGFR expression, improving treatment sensitivity.
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