Targeting oncogenic fusion-driven NUT carcinoma with CRISPR-Cas9 genome editing

TL;DR

This study shows that CRISPR-Cas9 can disrupt a cancer-causing gene fusion in NUT carcinoma, potentially leading to new and effective treatments.

Contribution

The study demonstrates CRISPR-Cas9's effectiveness in directly targeting and disrupting the BRD4::NUTM1 fusion gene in NUT carcinoma.

Findings

CRISPR-Cas9 successfully disrupted the BRD4::NUTM1 fusion gene in NUT carcinoma cell lines.

Genetic disruption led to reduced cell proliferation, cell-cycle arrest, and apoptosis in cancer cells.

The results suggest CRISPR-based strategies could be effective for treating fusion-driven cancers.

Abstract

NUT carcinoma (NC) is a highly aggressive malignancy characterized by an oncogenic fusion gene incorporating the NUTM1 gene. To date, no established treatment options exist. CRISPR-Cas9 technology allows precise genomic targeting, thereby presenting a promising therapeutic strategy for cancers with well-defined genomic alterations such as oncogenic fusion genes. In this study, we investigated the effects of CRISPR-Cas9-mediated disruption of the BRD4::NUTM1 fusion gene in NC cell lines using multiple single guide RNAs (sgRNAs) to target different sites of both fusion partner genes. Our experiments identified promising sgRNA candidates that were shown to successfully disrupt the BRD4::NUTM1 fusion gene at the DNA level, thus leading to an efficient knockout of the aberrant fusion protein. This genetic disruption resulted in profound functional impairments in NC cells, which included a significant reduction in proliferative capacity, cell-cycle arrest, and induction of apoptosis. These findings underscore the dependency of NC on the BRD4::NUTM1 fusion gene and highlight the potential of CRISPR-based strategies for targeting cancer at its genetic level. This approach also holds promise for the development of highly specific and effective therapies for many other oncogenic fusion driven cancers.

NUT carcinoma depends on the BRD4::NUTM1 fusion, which current inhibitors can target but without durable clinical efficacy. This study demonstrates that CRISPR-Cas9 can directly disrupt this fusion, suppressing cancer cell growth. Therefore, cancer genome editing could be employed as an alternative and effective strategy for targeting fusion-driven solid cancers.

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