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Selective targeting of genome amplifications and repeat elements by CRISPR-Cas9 nickases to promote cancer cell death

Matthew B. Hanlon, Jason M. Shohet and Scot A. Wolfe ()
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Matthew B. Hanlon: University of Massachusetts Chan Medical School
Jason M. Shohet: University of Massachusetts Chan Medical School
Scot A. Wolfe: University of Massachusetts Chan Medical School

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Focal gene amplification serves as an oncogenic driver during tumorigenesis and is a hallmark of many forms of cancer. Oncogene amplifications promote genomic instability, which is integral to cancer cell survival and evolution. However, focal gene amplification potentially affords an opportunity for therapeutic exploitation. As a proof-of-concept, we leverage CRISPR-Cas9 nickase to selectively promote cancer cell death in MYCN-amplified neuroblastoma in a gene amplification-dependent manner. Our analysis demonstrates that CRISPR-Cas9 nickase can generate a lethal number of highly toxic, replication-dependent double-strand breaks in cells harboring amplified loci. Furthermore, we demonstrate that Cas9 nickase—mediated toxicity can be modulated in combination with small molecule inhibitors targeting key regulators of the DNA-damage response or cell death pathways. Importantly, our findings in MYCN-amplified neuroblastoma translate to other cancer types with distinct oncogene amplifications.

Date: 2025
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DOI: 10.1038/s41467-025-60160-2

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