Quadruple?editing of the MAPK and PI3K pathways effectively blocks the progression of KRAS?mutated colorectal cancer cells

Mutated KRAS promotes the activation of MAPK pathway and progression colorectal cancer (CRC) cells. Aberrant PI3K strongly attenuates efficacy suppression in KRAS-mutated CRC. The development a novel strategy targeting dual is therefore highly essential for therapy In this study, quadruple-depleting system KRAS, MEK1, PIK3CA, MTOR genes based on CRISPR/SaCas9 was developed. Adenovirus serotype 5 (ADV5) integrated with two engineered proteins, an adaptor protector, to form ADV-protein complex (APC) systemic delivery CRISPR system. Quadruple-editing could significantly inhibit pathways CRC cells oncogenic mutations PIK3CA or mutation compensated activation. Compared MEK PI3K/MTOR inhibitors, quadruple-editing induced more significant survival inhibition primary PIK3CA. specifically EpCAM hexon-shielding protector dramatically enhance ADV5 infection efficiency reduce off-targeting tropisms many organs except colon. Moreover, intravenously delivered by APC blocked tumor growth cells, without influencing normal tissues cell- patient-derived xenograft models. Therefore, APC-delivered shows promising therapeutic potential