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

## TL;DR

This study identifies ELF2 as a gene linked to resistance against the chemotherapy drug topotecan in retinoblastoma, suggesting it could be a target for improving treatment.

## Contribution

The study reveals ELF2 as a novel gene associated with topotecan resistance in retinoblastoma through CRISPR-Cas9 screening and functional validation.

## Key findings

- ELF2 expression decreases in retinoblastoma cells resistant to topotecan, leading to reduced apoptosis.
- Disruption of ELF2 in a mouse model reduces the effectiveness of topotecan against tumors.
- ELF2-mediated resistance involves the MT-CYB pathway related to ATP synthesis.

## 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.