Combining Multiplexed CRISPR/Cas9-Nickase and PARP Inhibitors Efficiently and Precisely Targets Cancer Cells
Year: 2025
Type: article
Abstract: 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.
Source: Cancer Research
Authors: Soyoung Lee, Kyunghwan Kim, Hye-Jin Jeong, Subin Choi, Himchan Cheng, Dayoung Kim, Soomin Heo, Jinhee Mun, Minjong Kim, Eunjin Lee, Yoon Ji Choi, Seon-gyeong Lee, Eun A Lee, Yewon Jang, Kayeong Lim, Heon Seok Kim, Euihwan Jeong, Seung-Jae Myung, Deok-Beom Jung, Chang Sik Yu, In Ho Song, M. Ryan Corces, Joo H. Kang, Kyungjae Myung, Taejoon Kwon, Tae-Eun Park, Jinmyoung Joo, Seung Woo Cho
Institutions: Institute for Basic Science, Ulsan National Institute of Science and Technology, Korean Association Of Science and Technology Studies, Korea Institute of Science and Technology, Hanyang University, Asan Medical Center, University of Ulsan, Gladstone Institutes, University of California, San Francisco
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
OpenAlex ID: W4410115078