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나노의학 연구단
나노의학 연구단
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Targeting mutant &ITKRAS&IT with CRISPR-Cas9 controls tumor growth

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Title
Targeting mutant &ITKRAS&IT with CRISPR-Cas9 controls tumor growth
Author(s)
Wonjoo Kim; Sangeun Lee; Han Sang Kim; Minjung Song; Yong Hoon Cha; Young-Hoon Kim; Jeonghong Shin; Eun-Seo Lee; Yeonsoo Joo; Jae J. Song; Eun Ju Choi; Jae W. Choi; Jinu Lee; Moonkyung Kang; Jong In Yook; Min Goo Lee; Yeon-Soo Kim; Soonmyung Paik; Hyongbum (Henry) Kim
Publication Date
2018-03
Journal
GENOME RESEARCH, v.28, no.3, pp.374 - 382
Publisher
Cold Spring Harbor Laboratory Press
Abstract
KRAS is the most frequently mutated oncogene in human tumors, and its activating mutations represent important therapeutic targets. The combination of Cas9 and guide RNA from the CRISPR-Cas system recognizes a specific DNA sequence and makes a double-strand break, which enables editing of the relevant genes. Here, we harnessed CRISPR to specifically target mutant KRAS alleles in cancer cells. We screened guide RNAs using a reporter system and validated them in cancer cells after lentiviral delivery of Cas9 and guide RNA. The survival, proliferation, and tumorigenicity of cancer cells in vitro and the growth of tumors in vivo were determined after delivery of Cas9 and guide RNA. We identified guide RNAs that efficiently target mutant OAS without significant alterations of the wild-type allele. Doxycycline-inducible expression of this guide RNA in KRAS-mutant cancer cells transduced with a lentiviral vector encoding Cas9 disrupted the mutant KRAS gene, leading to inhibition of cancer cell proliferation both in vitro and in vivo. Intra-tumoral injection of lentivirus and adeno-associated virus expressing Cas9 and sgRNA suppressed tumor growth in vivo, albeit incompletely, in immunodeficient mice. Expression of Cas9 and the guide RNA in cells containing wild-type KIZAS did not alter cell survival or proliferation either in vitro and in vivo. Our study provides a proof-of-concept that CRISPR can be utilized to target driver mutations of cancers in vitro and in vivo © 2018 Kim et al.
URI
https://pr.ibs.re.kr/handle/8788114/4629
ISSN
1088-9051
Appears in Collections:
Center for Nanomedicine (나노의학 연구단) > Journal Papers
Files in This Item:
27.Genome Research 28, 374-382, (2018).pdfDownload

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