Gene amplifications are an oncogenic driver utilized by many forms of
cancer in tumor development or treatment relapse. Promoting genomic
instability or the proclivity to propagate genomic alterations through acquired defects in
DNA repair machinery, replication licensing, or
cell cycle control,
gene amplifications not only drive oncogenesis, but also afford an opportunity for therapeutic exploitation. Here,
CRISPR-Cas9 nickases are disclosed which selectively promote
cancer cell death in a
gene amplification-
dependent manner. For example,
CRISPR- Cas9 nickases generate a lethal number of highly toxic single-ended double-strand breaks within the
genome of proliferating
cancer cells harboring amplified genomic loci during
DNA replication. Cas9 nickases may serve as a tumor-selective therapeutic that mitigates the collateral damage observed with conventional chemoradiotherapies and avoids chemoresistance.