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However, its tumoricidal potential remains unclear, especially in comparison with therapeutic doses of radiation. Here, we demonstrate that CRISPR\/Cas9-induced DSBs are more cytotoxic in PCs than a comparable number of radiation-induced DSBs. We observed more than 90% tumor growth inhibition by targeting 9 sites with cancer-specific sgRNAs. Through both bioinformatics and cytogenetics analyses, we found that CRISPR\/Cas9-induced DSBs triggered ongoing chromosomal rearrangements, with 87% of structural variants not directly produced from the initial CRISPR\/Cas9-induced DSBs, and chromosomal instability peaking before cell death. By comparing the cytotoxicity of CRISPR\/Cas9- and radiation-induced DSBs, we demonstrated that the number of DSBs required to achieve equitoxic effects was approximately 3 times higher for radiation than CRISPR\/Cas9. Finally, we showed that PC cells that had survived CRISPR\/Cas9 targeting retained susceptibility to subsequent CRISPR\/Cas9-induced DSBs at different genomic sites with more than 87% growth inhibition. Together, our data support the therapeutic potential of CRISPR\/Cas9 as an anticancer strategy.<\/jats:p>\n                  <jats:p\/>\n                  <jats:p>The CRISPR-Cas9 system can be adapted into a cancer killing strategy by inducing precise and unrecoverable DNA damage.<\/jats:p>","DOI":"10.1172\/jci190121","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T15:53:37Z","timestamp":1779206017000},"source":"Crossref","is-referenced-by-count":1,"title":["Simultaneous CRISPR\/Cas9-induced double-strand breaks are lethal in models of pancreatic cancer"],"prefix":"10.1172","volume":"136","author":[{"given":"Selina Shiqing K.","family":"Teh","sequence":"first","affiliation":[{"name":"Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akhil","family":"Kotwal","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology and Molecular Radiation Sciences; 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