Lee, Soyoung Kim, Kyunghwan Jeong, Hye-Jin Choi, Subin Cheng, Himchan Kim, Dayoung Heo, Soomin Mun, Jinhee Kim, Minjong Lee, Eunjin Choi, Yoon Ji Lee, Seon-gyeong Lee, Eun A. Jang, Yewon Lim, Kayeong Kim, Heon Seok Jeong, Euihwan Myung, Seung-Jae Jung, Deok-Beom Yu, Chang Sik Song, In Ho Corces, M. Ryan Kang, Joo H. Myung, Kyungjae Kwon, Taejoon Park, Tae-Eun Joo, Jinmyoung Cho, Seung Woo 2025-08-31T03:00:28Z 2025-08-31T03:00:28Z 2025-08-27 2025-08 0008-5472 https://pubs.kist.re.kr/handle/201004/153077 Triggering cancer cell death by inducing DNA damage is the primary aim of radiotherapy; however, normal cells are also damaged. In this study, we showed that delivery of only four synthetic guide RNAs with Cas9 endonuclease efficiently induced simultaneous DNA double-strand breaks, resulting in efficient cell death in a cell type-specific manner. Off-target effects of Cas9 endonuclease were prevented by using Cas9-nickase to induce DNA single-strand breaks and blocking their repair with PARP inhibitors (PARPi). When recombinant Cas9-nickase protein and multiple synthetic guide RNAs were delivered with PARPis into cultured cells, in vivo xenografts, and patient-derived cancer organoids via lipid nanoparticles, cancer cells were unable to tolerate the induced DNA damage even in the presence of a functional BRCA2 gene. This approach has the potential to expand the use of PARPis with verified safety and thus is a potentially powerful tool for personalized genome-based anticancer therapy.Significance: Targeting cancer-specific variants with CRISPR/Cas9-nickase induces cancer-specific cell death in combination with DNA repair pathway inhibitors, demonstrating the potential of CRISPR cancer therapy for treating a broad range of cancers. English American Association for Cancer Research Combining Multiplexed CRISPR/Cas9-Nickase and PARP Inhibitors Efficiently and Precisely Targets Cancer Cells Article 10.1158/0008-5472.CAN-24-2938 1 Cancer Research, v.85, no.15, pp.2890 - 2904 Cancer Research 85 15 2890 2904 N scie scopus 001549886800009 2-s2.0-105012883864 Oncology Oncology Article DNA-REPAIR RNA