Cell death & diseaseDec 23, 2025

Loss of ELF2 may cause resistance to topotecan in retinoblastoma cancer

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jun 27, 2026

Abstract

Essence

Loss of ELF2 appears to make retinoblastoma cells less sensitive to topotecan by reducing apoptosis and shifting ATP-synthesis-related signaling.

Evidence

This translational preclinical study used genome-wide CRISPR-Cas9 screening, retinoblastoma cell assays, a mouse xenograft model, RNA sequencing, and a patient tumor-volume correlation after topotecan.

Caveat

The patient component is correlative and the resistance mechanism is mainly shown in cells and xenografts, so ELF2 is not yet a validated therapeutic target.

Simplified

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.