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Liver cancer is the sixth most common cancer worldwide and the third leading cause of cancer-related death
.
Despite promising initial responses to molecularly targeted therapy, tumors are often prone to drug resistance
The study used the CombiGEM-CRISPR v2.
0 screening platform to generate multiplex gene knockouts, which rapidly characterized cancer cell survival by double knockout in a pool of cells linked to DNA barcodes
.
DNA barcodes specify the type of genetic alterations that cancer cells carry
By combining CRISPR-Cas9 screening, focusing on a set of drug targets whose expression is upregulated in HCC cancer stem cells, the Hong Kong Polytechnic University research team found that the two combinations contained the common target NMDAR1, and the paired targets were two kinases (FLT4 and FGFR3) , and the corresponding inhibitors are all one-clone rafenib
.
Specifically, genetically removing established gene combinations inhibited the growth and self-renewal capacity of HCC cells
The team also revealed the enhanced inhibitory effect of the corresponding drug combination and its underlying molecular mechanism
.
The combination of ifenprodil and sorafenib significantly reduced cell growth and stemness in multiple liver cancer cell lines, patient-derived organoids, and tumor xenograft models
Ifenprodil has been used as a vasodilator in countries such as Japan and France, which have a known history of human safety
.
Combined with first-line sorafenib, the HKUMed research team successfully demonstrated that these two drug regimens can significantly inhibit the growth and self-renewal capacity of HCC cells
"Successful drug repurposing saves the cost and time required to develop new drugs whose efficacy and safety are uncertain
.
" The drug combination could easily be tested in future HCC treatment trials
The application scope of the CombiGEM-CRISPR v2.
Journal Reference :
Feng Xu, Man Tong, Cindy SW Tong, Becky KC Chan, Hoi Yee Chu, Tin Lok Wong, John HC Fong, Maggie SH Cheung, Kylie Hin-Man Mak, Lakhansing Pardeshi, Yuanhua Huang, Koon Ho Wong, Gigi CG Choi, Stephanie Ma, Alan SL Wong.
