CRISPR disrupts KRAS oncogene

As the popular saying goes, “cancer is a disease of genes”. We now know that both cancer emergence and its progression is entirely dependent on dozens of mutated genes. Many methods target explicitly those elements – among them, there is an increasing interest in gene therapies, where mutated genes can be corrected or switched off.

Researchers from BGI-Shenzen company focused on the latter method. With CRISPR/Cas9, they identified mutated KRAS genes and disrupted their sequences near common oncogenic mutations. With dead Cas9, they switched off KRAS transcripts. Both methods were reported to be relatively free from side effects and highly specific for mutated KRAS only (wild-type, “healthy” KRAS was not affected).

The study targed G12S mutation, which was for the first time changed by CRISPR systems. KRAS with G12S is present in 2.56% of rectal carcinoma cases, 1.84% of colorectal adenocarcinoma cases, and 1.66% of colorectal carcinoma.

The authors performed experiments in cell lines, as well as in mice with human lung cancer xenografted into them. Local injection of adeno-associated virus with CRISPR/Cas9 reduced cancer volume by 46%.

Although the method is far from clinical setting, it can be seen as a proof-of-concept for preclinical development and testing of CRISPR-based cancer therapies. In addition to classic inhibition of one target, it can be extended to capture many different mutations or even numerous genes, which drive progress of an oncological disease.

Preprint: Qianqian Gao, Wenjie Ouyang, Bin Kang, Xu Han, Ying Xiong, Renpeng Ding, Yijian Li, Fei Wang, Lei Huang, Lei Chen, Dan Wang, Xuan Dong, Zhao Zhang, Yanshan Li, Baichen Ze, Yong Hou, Huanming Yang, Yuanyuan Ma, Ying Gu, Cheng-Chi Chao (2019). Selective targeting of an oncogenic KRAS mutant allele by CRISPR/Cas9 induces efficient tumor regression. Doi:10.1101/807578.

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