Gene editing particle system as a therapeutic approach for drug-resistant colorectal cancer

• Published in: Nano research Vol. 13; no. 6; pp. 1576 - 1585
• Main Authors: Ryu, Jee-Yeon, Choi, You Jung, Won, Eun-Jeong, Hui, Emmanuel, Kim, Ho-Shik, Cho, Young-Seok, Yoon, Tae-Jong
• Format: Journal Article
• Language: English
• Published: Beijing Tsinghua University Press 01-06-2020; Springer Nature B.V
• Subjects: Antibodies; Atomic/Molecular Structure and Spectra; Biomedicine; Biotechnology; Cancer; Cell death; Chemistry and Materials Science; Colorectal cancer; Colorectal carcinoma; Condensed Matter Physics; Drug resistance; Epidermal growth factor; Epidermal growth factor receptors; Genetic modification; Genome editing; Growth factors; K-Ras protein; Lipids; Materials Science; Monoclonal antibodies; Mutation; Nanotechnology; Point mutation; Research Article; Ribonucleic acid; RNA; Surgical implants; Targeted cancer therapy; Tumors; nanoliposome; mutation; drug-resistance; colorectal cancer; clustered regularly interspaced short palindromic repeat and associated Cas9 nuclease (CRISPR/Cas9)
• ISSN: 1998-0124; 1998-0000
• DOI: 10.1007/s12274-020-2773-1

The epidermal growth factor receptor (EGFR) pathway plays an important role in the progression of colorectal cancer (CRC). Anti-EGFR drugs based on antibodies have been widely used for treating CRC through inducing the cell death pathway. However, the majority of CRC patients will inevitably develop drug-resistance during anti-EGFR drug treatment, which is mainly caused by a point mutation in the
KRAS
oncogene. We developed a nanoliposomal (NL) particle containing the Cas9 protein and a single-guide RNA (sgRNA) complex (Cas9-RNP), for genomic editing of the
KRAS
mutation. The NL particle is composed of bio-compatible lipid compounds that can effectively encapsulate Cas9-RNP. By modifying the NL particle to include the appropriate antibody, it can specifically recognize EGFR expressing CRC and effectively deliver the gene-editing complexes. The conditions of NL treatment were optimized using a
KRAS
mutated CRC
in vivo
mouse model. Mice with
KRAS
-mutated CRC showed drug resistance against cetuximab, a therapeutic antibody drug. After treating the mice with the
KRAS
gene-editing NL particles, the implanted tumors showed a dramatic decrease in size. Our results demonstrated that this genomic editing complex has great potential as a therapeutic carrier system for the treatment of drug-resistant cancer caused by a point mutation.