Chromosomal instability induced by CRISPR/Cas9: implications for pancreatic cancer therapy
Li-Chan Chang, Christine E. Eyler, Chang-Lung Lee
Li-Chan Chang, Christine E. Eyler, Chang-Lung Lee
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Commentary

Chromosomal instability induced by CRISPR/Cas9: implications for pancreatic cancer therapy

Abstract

Clinical management of pancreatic cancer (PC) remains severely limited, primarily due to the complex tumor microenvironment. Emerging DNA damage–targeted strategies have demonstrated considerable therapeutic potential in PC. In this issue of the JCI, Teh et al. employed cancer-specific multitarget sgRNAs to induce DNA double-strand breaks (DSBs), resulting in lethal effects in PC cells. Integrative bioinformatic and cytogenetic analyses revealed that CRISPR/Cas9-mediated DSBs provoked persistent chromosomal instability, ultimately leading to chromosome catastrophe and cell death. Compared with equivalent radiation-induced DSBs, these sgRNAs exhibited superior cytotoxicity and were able to eliminate cells resistant to a specific sgRNA via subsequent targeting at distinct genomic sites, highlighting a promising and innovative precision therapeutic approach for clinical treatment of PC.

Authors

Li-Chan Chang, Christine E. Eyler, Chang-Lung Lee

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Figure 1

Anticancer strategies based on DNA DSBs induced by RT and CRISPR/Cas9 systems.

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Anticancer strategies based on DNA DSBs induced by RT and CRISPR/Cas9 sy...
(A) Conventional RT induces DNA damage in cancer cells through both direct ionization and indirect effects mediated by ROS, among which DSBs are the most lethal form. This process occurs rapidly (within hours), and DNA repair pathways — including nonhomologous end joining, homologous recombination, and microhomology-mediated end joining (MMEJ) — are promptly activated. Insufficient or failed repair subsequently leads to cell death through multiple pathways. Clinically, therapeutic efficacy can be enhanced by increasing the extent of DSBs and/or inhibiting DNA repair mechanisms. (B) The strategy reported by Teh et al. (12) induced simultaneous CRISPR/Cas9-mediated DSBs using cancer-specific protospacer adjacent motif–guided (PAM-guided) multitarget sgRNAs delivered into Cas9-expressing cancer cells. This approach induced persistent DSB formation and continuous DNA repair over several days, leading to genome-wide structural variations and ongoing chromosomal rearrangements. As chromosomal instability (CIN) accumulated and reached a critical threshold, cells underwent polyploidization and developed severe chromosomal aberrations — a process collectively referred to as chromosome catastrophe — ultimately resulting in delayed cell death via apoptosis.