Loss of ELF2 drives topotecan resistance in retinoblastoma revealed by genome-wide CRISPR-Cas9 screening

  • Cell Death Dis. 2025 Dec 23. doi: 10.1038/s41419-025-08335-z.
Jingyi Jiang  #  1  2 ,  Zihua Jiang  #  1  2 ,  Qian Luo  #  1  2 ,  Xi Chen  1  2 ,  Jiejie Zhuang  1  2 ,  Jiaxin Chen  1  2 ,  Qingqing Mu  1  2 ,  Jin Qiu  1  2 ,  Yan Li  1  2 ,  Shuxia Chen  1  2 ,  Ping Zhang  1  2 ,  Keming Yu  1  2 ,  Shuilian Chen  3  4 ,  Guei-Sheung Liu  5  6  7 ,  Jing Zhuang  8  9
Affiliations
  • 1. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China.
  • 2. Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, China.
  • 3. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China. [email protected].
  • 4. Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, China. [email protected].
  • 5. Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC, Australia. [email protected].
  • 6. Ophthalmology, Department of Surgery, University of Melbourne, East Melbourne, VIC, Australia. [email protected].
  • 7. Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia. [email protected].
  • 8. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China. [email protected].
  • 9. Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, China. [email protected].
  • # Contributed equally.
PMID: 41436498 DOI: 10.1038/s41419-025-08335-z
Abstract

The Topoisomerase I inhibitor topotecan is an effective chemotherapeutic agent for retinoblastoma; however, treatment resistance remains a major clinical challenge, and its mechanisms remain elusive. Using genome-wide CRISPR-Cas9 knockout screening, we identified ELF2 as a key gene involved in topotecan resistance. Here, we show that surviving retinoblastoma cells exposed to topotecan showed progressively decreased ELF2 expression, accompanied by reduced Apoptosis. In a mouse xenograft model, ELF2 disruption diminished the antitumor efficacy of topotecan, with ELF2-knockout cells exhibiting reduced topotecan-induced Apoptosis. RNA Sequencing further revealed that the MT-CYB pathway, associated with ATP synthesis, contributes to ELF2-mediated resistance. Importantly, clinical analysis demonstrated a correlation between ELF2 expression and tumor volume in retinoblastoma patients treated with topotecan. Together, these findings interrogate the mechanisms underlying topotecan resistance in retinoblastoma and suggest ELF2 as a potential therapeutic target to overcome drug resistance.

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