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 ce...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.展开更多
基金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)+1 种基金partially supported by the GRRC program of Gyeonggi province(GRRC 2016B02,Photonics-Medical Convergence Technology Research Center)was partly supported by grant(No.2019R1F1A1058879)from the National Foundation Research of Korea.
文摘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.
