2. Academic Validation
  3. Combining Multiplexed CRISPR/Cas9-Nickase and PARP Inhibitors Efficiently and Precisely Targets Cancer Cells

Combining Multiplexed CRISPR/Cas9-Nickase and PARP Inhibitors Efficiently and Precisely Targets Cancer Cells

  • Cancer Res. 2025 Aug 1;85(15):2890-2904. doi: 10.1158/0008-5472.CAN-24-2938.
Soyoung Lee # 1 2,  Kyunghwan Kim # 1 3,  Hye-Jin Jeong # 2,  Subin Choi 2,  Himchan Cheng 2,  Dayoung Kim 2,  Soomin Heo 1 2,  Jinhee Mun 2,  Minjong Kim 4,  Eunjin Lee 2,  Yoon Ji Choi 5,  Seon-Gyeong Lee 6,  Eun A Lee 1,  Yewon Jang 1,  Kayeong Lim 7,  Heon Seok Kim 8,  Euihwan Jeong 6 9,  Seung-Jae Myung 10 11 12,  Deok-Beom Jung 11,  Chang Sik Yu 13,  In Ho Song 13,  M Ryan Corces 14 15 16,  Joo H Kang 2,  Kyungjae Myung 1 2,  Taejoon Kwon 1 2 6 9 17,  Tae-Eun Park 2,  Jinmyoung Joo 1 2 17,  Seung Woo Cho 1 2 17
Affiliations

Affiliations

  • 1 Center for Genomic Integrity, Institute for Basic Science, Ulsan, Republic of Korea.
  • 2 Department of Biomedical Engineering, College of Information and Biotechnology, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
  • 3 Department of Chemistry, College of Natural Science, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
  • 4 Department of Biological Science, College of Information and Biotechnology, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
  • 5 In Vivo Research Center, UNIST Central Research Facilities, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
  • 6 Division of Research and Development, CasCure Therapeutics, Seoul, Republic of Korea.
  • 7 Brain Science Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea.
  • 8 Department of Life Science, College of Natural Science, Hanyang University, Seoul, Republic of Korea.
  • 9 CasCure Therapeutics, Ulsan, Republic of Korea.
  • 10 Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
  • 11 Digestive Diseases Research Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
  • 12 EDIS Biotech, Seoul, Republic of Korea.
  • 13 Division of Colon and Rectal Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
  • 14 Gladstone Institute of Neurological Disease, San Francisco, California.
  • 15 Gladstone Institute of Data Science and Biotechnology, San Francisco, California.
  • 16 Department of Neurology, University of California San Francisco, San Francisco, California.
  • 17 Graduate School of Health Science and Technology, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
  • # Contributed equally.
PMID: 40327605 DOI: 10.1158/0008-5472.CAN-24-2938
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.

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