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

Abstract

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.

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Acknowledgements

This work was supported by the Industrial Strategic Technology Development Program (Project No. 10047679) of the Ministry of Trade, Industry & Energy (MI, Republic of Korea), partially supported by the GRRC program of Gyeonggi province (GRRC 2016B02, Photonics-Medical Convergence Technology Research Center), and was partly supported by grant (No. 2019R1F1A1058879) from the National Foundation Research of Korea.

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Correspondence to Young-Seok Cho or Tae-Jong Yoon.

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Ryu, J., Choi, Y.J., Won, E. et al. Gene editing particle system as a therapeutic approach for drug-resistant colorectal cancer. Nano Res. 13, 1576–1585 (2020). https://doi.org/10.1007/s12274-020-2773-1

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Keywords

  • nanoliposome
  • clustered regularly interspaced short palindromic repeat and associated Cas9 nuclease (CRISPR/Cas9)
  • KRAS mutation
  • drug-resistance
  • colorectal cancer